Process for 1,4-dihydropyridine compounds

ABSTRACT

The invention relates to a process for producing new compounds of formula I: ##STR1## and isomers thereof, as well as acid addition salts thereof, in which the symbols have the meanings set forth in the specification.

This application is a continuation in part of our prior-filed copendingapplication Ser. No. 081,303 filed Aug. 3, 1987, now U.S. Pat. No.4,870,091, issued Sept. 26, 1989.

The present invention relates to new 1,4-dihydropyridine compounds, tothe processes for preparing them and to pharmaceutical compositionscontaining them.

Some 1,4-dihydropyridine compounds such as nifedipine (U.S. Pat. No.3,485,847) and amlodipine (Publication EP No. 89,167) with usefulpharmacological properties, especially as inhibitors of calciummovements across membranes and into cells are known. Other compounds of2-alkoxymethyl-1,4-dihydropyridine derivatives in which the ether-boundgroup is substituted with aliphatic or aromatic heterocycles containingone or more nitrogen atoms (Publications EP No. 100,189, EP No. 106,462,EP No. 107,293, EP No. 132,375, EP No. 172,029, EP No. 164,247 and EPNo. 150,939) or with aminoalkyl (Publications EP No. 116,769, EP No.60,674 and EP No. 119,050) or hydroxyalkyl (Publication EP No. 161,917)groups are known.

Moreover, 2-methyl- and 2-aminomethyl-1,4-dihydropyridine compounds aredescribed in Publication EP No. 145,434. Some2-aminoalkyl-1,4-dihydropyridine compounds are also known (PublicationDE No. 2,844,595 and Application JP No. 80/47,656).

The compounds of the present invention are distinguishable from other1,4-dihydropyridines known in the state of the art, by their structureand by their pharmacological activity. In fact, the compounds of theinvention are strong inhibitors of calcium movements across membranes,with a very long lasting activity, thus making it possible to offertreatments with a single daily intake.

More particularly, the present invention relates to 1,4-dihydropyridinecompounds of formula I: ##STR2## in which:

Ar represents a phenyl radical optionally containing one to fiveidentical or different substituents, each representing a halogen atom,an alkoxy radical containing 1 to 4 carbon atoms, an alkylthio radicalcontaining 1 to 4 carbon atoms, a trihalomethyl radical or amethylenedioxy radical,

Y, Z, Y₁ and Z₁, which may be identical or different, each represent ahydrogen atom, a straight-chain or branched lower alkyl radicalcontaining 1 to 4 carbon atoms, a cyclopropyl radical, adicyclopropylmethyl radical, a 2,2-dicyclopropylethyl radical, a2,2-dicyclopropylethenyl radical, a 3,3-dicyclopropylpropyl radical, a3,3-dicyclopropyl-1-propenyl radical, a straight-chain or branchedalkenyl radical containing 2 to 5 carbon atoms or a phenyl radicaloptionally substituted with a nitro radical,

W represents a straight-chain or branched lower alkyl radical containing1 to 4 carbon atoms or a lower alkoxymethyl radical containing 2 to 5carbon atoms,

V represents a methylene radical or an oxygen atom,

U represents a methyleneoxy radical or an ethyleneoxy radical when Vrepresents an oxygen atom, or a methylene radical when V also representsa methylene radical,

m and n, which may be identical or different, represent an integer whichmay take the values from 1 to 4,

R₁ and R₂, which may be identical or different, each represent ahydrogen atom, a straight-chain or branched lower alkyl radicalcontaining 1 to 4 carbon atoms, or a straight-chain or branched loweralkenyl radical containing 2 to 4 carbon atoms, a trihaloacetyl radical,on condition, however, that V never represents a methylene radical inthis case, a phenalkyl radical containing 7 to 10 carbon atoms,optionally substituted on the aromatic ring with one or more alkyl oralkoxy radicals containing 1 to 4 carbon atoms or with one or morehydroxy radicals, a 1-hydroxy-2-phenylethyl radical optionallysubstituted on the aromatic ring with one or more alkyl or alkoxyradicals containing 1 to 4 carbon atoms or with one or more hydroxyradicals or form, together with the nitrogen atom to which they areattached, a phtalimido group, in the racemic form or in the form ofoptical isomers, and to the addition salts thereof with apharmaceutically acceptable inorganic or organic acid, and to thequaternary ammonium salts thereof, formed with a lower alkylene or alkylhalide containing 1 to 4 carbon atoms when they contain a tertiaryamine.

The present invention also relates to the process for the preparation ofthe compounds of formula I, wherein:

either a compound of general formula II: ##STR3##

in which the definition of the substituents Y₁, Z₁ and W remains thesame as that defined previously in the case of general formula I, iscondensed

with a keto ester of general formula III: ##STR4##

in which Y, Z, U, V, m and n have the meaning defined above in formula Iand R'₁ and R'₂ represent a methyl radical and a benzyl radical, or ahydrogen atom and a trihaloacetyl radical, on condition, however, that Vnever simultaneously represents a methylene radical in this case, orform, together with the nitrogen atom to which they are attached, aphthalimido radical

and with an aromatic aldehyde of general formula IV:

    Ar--CHO                                                    (IV)

in which the definition of Ar remains the same as that definedpreviously in the case of general formula I, in a polar organic solventsuch as a primary or secondary alcohol or an organic acid, of lowmolecular weight, and at a temperature between 40° C. and 100° C., so asto obtain a compound of general formula I': ##STR5##

in which the definition of Ar, Y, Z, Y₁, Z₁, W, U, V, m and n remainsthe same as that mentioned above and the definition of R'₁ and R'₂remains identical to that given for R'₁ and R'₂ in general formula III,or

a keto ester of general formula V: ##STR6##

in which the definition of Y₁, Z₁ and W remains identical to that givenin the case of formula I, is condensed

with a compound of general formula VI: ##STR7##

in which Y, Z, U, V, m and n have the meaning defined above in the caseof formula I, and the definition of R'₁ and R'₂ remains identical tothat given in the case of general formula III

and with an aromatic aldehyde of general formula IV,

in a polar organic solvent such as a primary or secondary alcohol or anorganic acid, of low molecular weight, and at a temperature between 40°and 100° C.,

so as to obtain a compound of general formula I', or

a benzylidene of general formula VII: ##STR8##

in which the definition of Y₁, Z₁, W and Ar remains identical to thatgiven in the case of formula I, is condensed

with a compound of general formula VI, in a polar organic solvent suchas a primary or secondary alcohol or an organic acid, of low molecularweight and at a temperature between 40° and 100° C.,

so as to obtain the compounds of general formula I',

and subsequently, the compounds of general formula I'

in which the meaning of Ar, Y, Z, Y₁, Z₁, W, U, V, m and n remains thesame as that mentioned above and R₁ and R₂ represent a hydrogen radicaland a trihaloacetyl radical, or form, together with the nitrogen atom towhich they are attached, a phthalimido radical,

are subjected, if required,

to the action of hydrazine or a basic inorganic salt such as potassiumcarbonate, in the presence of water, in a water-miscible, low molecularweight, polar alcoholic solvent, and at a temperature between 40° and100° C.

so as to obtain the compounds of general formula I,

in which Ar, Y, Z, Y₁, Z₁, W, U, V, m and n have the meaning definedabove and R₁ and R₂ represent a hydrogen atom, and subsequently,

if required, they are either

subjected to the action of an arylethylene oxide of general formulaVIII: ##STR9##

in which K represents a phenyl radical, optionally substituted with oneor more alkyl or alkoxy radicals containing 1 to 4 carbon atoms or oneor more hydroxy radicals,

so as to obtain a compound of general formula I": ##STR10##

in which the meaning of Ar, Y, Z, Y₁, Z₁, W, U, V, m and n remainsidentical to that mentioned above and the meaning of K remains identicalto that given in the case of general formula VIII, or

subjected to the action of an alkylating agent of general formula IX:

in which X represents a halogen atom and R represents a straight-chainor branched lower alkyl or alkylene radical containing 1 to 4 carbonatoms,

in a polar organic solvent such as acetonitrile, in the presence of abasic inorganic salt such as potassium carbonate, at a temperaturebetween 40° and 100° C.,

so as to obtain the compounds of general formula I in which Ar, Y, Z,Y₁, Z₁, W, U, V, m and n have the same meaning as that defined above andR₁ and R₂ are identical and have the same meaning as R in generalformula IX, or alternatively

subjected first to the action of benzaldehyde in the presence of aninert and apolar aromatic solvent such as benzene, at a temperaturebetween 50°-120° C., and then, after removing the solvent employed, tothe action of sodium borohydride, in the presence of a low molecularweight polar aliphatic alcohol, so as to obtain a compound of generalformula I

in which the meaning of Ar, Y, Z, Y₁, Z₁, W, U, V, m and n remainsidentical to that mentioned above, R₁ represents a hydrogen atom and R₂a benzyl radical, which is subsequently

subjected, if required, to the action of an alkylating agent of generalformula IX,

so as to obtain a compound of general formula I

in which Ar, Y, Z, Y₁, Z₁, W, U, V, m and n have the meaning definedabove, the definition of R₁ is identical to that of R in general formulaIX and R₂ represents a benzyl radical, in the form of quaternaryammonium or tertiary amine salts, which is subsequently

subjected, if required, to the action of lithium triethylborohydride orto a catalytic hydrogenation so as to obtain, with the quaternaryammonium or tertiary amine salts respectively, the compounds of generalformula I in which Ar, Y, Z, Y₁, Z₁, W, U, V, m and n have the samemeaning as defined above, R₁ having the same meaning as R in generalformula IX and R₂ representing a benzyl radical or a hydrogen atomrespectively,

and then it is subjected, if required, to the action of an alkylatingagent of general formula IX,

so as to obtain the compounds of general formula I,

in which R₁ and R₂, which may be identical or different, each representa straight-chain or branched lower alkyl radical containing 1 to 4carbon atoms or a straight-chain or branched alkylene radical containing1 to 4 carbon atoms and subsequently

the compounds of general formula I are converted, if required, into anaddition salt with a pharmaceutically acceptable organic or inorganicacid,

or, in the case where they carry a tertiary amine in position 2 on theirside chain, into a quaternary ammonium salt with a halogenated alkyl oralkylene of general formula IX.

The compounds of general formula II may be obtained according to themethod described by CELERIER et al (Synthesis, 1981, p. 130-133).

The compounds of general formula III may be obtained by treating thecompounds of general formula X: ##STR11##

in which U, V, m and n and R₁ ' and R₂ ' have the meaning defined abovein the case of formula III,

with an acid chloride, followed by a condensation with Meldrum's acid inthe presence of pyridine

so as to obtain the compounds of general formula XI: ##STR12##

in which the definition of U, V, m, n, R'₁ and R'₂ remains identical tothat given above. The compounds of general formula XI are then subjectedto the action of an alcohol of general formula XII: ##STR13##

in which Y and Z have the meaning defined above in the case of generalformula I, at a temperature between 40°-150° C., so as to obtain thecompounds of general formula III.

The preparation of the compounds of general formula X is known(Carbohydrate Research, 1981, 88, p. 213-221).

Alternatively, and when, in general formula III, U and V represent anoxygen atom, they may also be prepared according to the method describedby C. TROOSTWIJK and R. KELLOGG (J.C.S. Chem. Comm., 1977, p. 932-933).

The compounds of general formula V may also be prepared by thecondensation of an acid chloride of general formula XIII:

    WCOCL                                                      (XIII)

in which W has the same meaning as in the case of general formula I,with Meldrum's acid. The products resulting from this reaction are thensubjected to the action of an alcohol of general formula XII so as togive the compounds of general formula V.

The compounds of general formula VI may be obtained by the action ofammonium acetate on the compounds of general formula III, in a polaralcohol and at a temperature between 50° and 100° C.

The compounds of general formula VII may be obtained by the condensationof the compounds of general formula V with an aromatic aldehyde ofgeneral formula IV (Can. J. Chem., 1967, 45, p. 1001).

The process for obtaining secondary amines from quaternary ammoniumsalts after reacting with lithium triethylborohydride is known (J. Org.Chem. 1975, 40, No. 4, p. 532). Similarly, the alkylation of primaryamines with arylethylene oxides of general formula VIII is described inthe literature (Tetra. Let. 1986, 27, No. 22, p. 2451-2454).

The optical isomers of the products of general formula I which form thesubject of the present invention may be obtained by known methods.

The different processes of separation of isomers or of steroselectivesynthesis described in the literature do not enable the isomers of2-{[2-(2-aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine,a compound of general formula I, to be obtained in a good yield. It washence necessary to invent a new process.

The subject of the present invention is also the process for preparingthe(-)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine,wherein 2-[2-(2-chloroethoxy)ethoxy]ethanol is condensed with potassiumphthalimide, in dimethylformamide in the heated state, to form2-[2-(2-phtalimidoethoxy)ethoxy]ethanol the compound of the formula XIV:##STR14## which is converted by means of Jones reagent to2-[2-(2-phtalimidoethoxy)ethoxy]acetic acid, the compound of the formulaXV: ##STR15## which is treated with carbonyldiimidazole and Meldrum'sacid in the presence of pyridine in methylene chloride to obtain thecompound of formula XVI: ##STR16## which is then reacted with(R)-2-phenyl-2-methoxyethanol, the compound of formula XVII: ##STR17##to obtain the β-keto ester of formula XVIII: ##STR18## which iscondensed in the presence of ammonium formate in ethanol with abenzylidene compound of formula XIX: ##STR19## to obtain(4R,4'R/4S,4'R)-4-(2,3-dichlorophenyl)-5-methoxycarbonyl-3-(2-methoxy-2-phenylethoxycarbonyl)-6-methyl-2-{[2-(2-phthalimidoethoxy)ethoxy]methyl}-1,4-dihydropyridine,the compound of formula XX: ##STR20##

and then:

either:

this compound is subjected to the action of aqueous sodium bicarbonatesolution, in solution in acetonitrile, to obtain(4R,4'R/4S,4'R)-2-[{2-[2-(2carboxyphenylcarboxamido)ethoxy]ethoxy}methyl]-4-(2,3-dichlorophenyl)-5-methoxycarbonyl-3-(2-methoxy-2-phenylethoxycarbonyl)-6-methyl-1,4-dihydropyridine,the compound of formula XXI: ##STR21## which is treated, afterseparation by HPLC, with a mixture of glyme and sodium ethylate toobtain a mixture containing(-)-2-[{2-[2-(2-carboxyphenylcarboxamido)-ethoxy]ethoxy}methyl]-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine,the compound of formula XXII: ##STR22## and its homolog substituted atthe 5-position with an ethoxycarbonyl radical, or:

the compound of formula xx is separated by chromatography on a silicacolumn, using a mixture of methylene chloride and ethyl acetate (95:5V/V) as eluant, to obtain the less polar isomer of4-(2,3-dichlorophenyl)-5-methoxycarbonyl-3-(2-methoxy-2-phenylethoxycarbonyl)-6-methyl-2-{[2-(2-phthalimidoethoxy)ethoxy]methyl}-1,4-dihydropyridine,which is then subjected to the action of sodium ethanolate in thepresence of glyme in solution in ethanol to obtain a mixture containingthe compound of formula XXII and its homolog substituted at the5-position with an ethoxycarbonyl radical, which is then subjected tothe action of carbonyldiimidazole in solution in a halogenated alkane atroom temperature to obtain a mixture containing(-)-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-{[2-(2-phtalimidoethoxy)ethoxy]methyl}-1,4-dihydropyridine,the compound of formula XXIII: ##STR23## and its homolog substituted atthe 5-position with an ethoxycarbonyl radical, which mixture is thenseparated by HPLC to obtain pure(-)-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-{[2-(2-phtalimidoethoxy)ethoxy]methyl}-1,4-dihydropyridine,which is then brought to reflux in ethanol in the presence of hydrazinehydrate to give(-)-2-{[2-(2-aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-di-hydropyridine,which can then be salified with a pharmaceutically compatible organic orinorganic acid.

(R)-2-Phenyl-2-methoxyethanol, the compound of formula XVII is obtainedby reduction of the optically active corresponding acid. The lattercompound is prepared according to the process described in J. Chem. Soc.1962, p. 1519.

2-(2,3-Dichlorobenzylidene)-3-oxobutanoic acid methyl ester, thecompounds of formula XIX, is obtained by condensation of2,3-dichlorobenzaldehyde with methyl acetoacetate.

Among the pharmaceutically acceptable acids for the preparation of theaddition salts of the compounds of general formula I, there may bementioned phosphoric, hydrochloric, citric, oxalic, maleic, sulfuric,tartaric, mandelic, fumaric, methanesulfonic, camphosulfonic,benzenesulfonic, acids and the like.

The compounds according to the invention and the addition or thequaternary ammonium salts thereof are endowed with highly valuablepharmacological properties and are distinguishable form other1,4-dihydropyridine derivatives which are already known.

In fact, in vitro pharmacological trials have shown that these compoundsare strong inhibitors of calcium penetration into cells.

Intracellular calcium concentration plays a messenger role in manybiological functions: contractions and secretions; this concentrationlargely depends on calcium movement across membranes, which, as it isvery concentrated in the extracellular media, is conveyed through thecalcium-selective channels located in the membrane.

Thus, inhibitors of these channels which restrict or stop thepenetration of calcium may have valuable therapeutical effects in manypathological conditions such as vasorelaxation, for the treatment ofarterial hypertension and pulmonary hypertension, and peripheral andcoronary muscular diseases (Am. J. Card. 1980, 46, p. 1047-1058;Burger's Medicinal Chemistry 4th Edition, Part III, p. 5456--John Wileyand Sons inc. U.S.A., 1981, Life Science, 1983, 33, p. 2571-2581).Induced beneficial effects are also observed in the treatment of cardiacinsufficiencies.

The modulation of myocardial contraction is also useful in cardiacischemic conditions (Medicine, 1985, 64, p. 61-73). The restriction ofcalcium penetration into cells may also play an important role inpreventing calcium accumulation which is characteristic of cell agingand which is related to some vascular degenerativediseases,--atheromatous diseases in particular--(Medicinal researchreview, 1985, 5, p. 394-425).

Calcium modulation is also of value in the treatment of epilepsy anddizzinesses of central origin. The restriction of ionized calcium in thesmooth fibers of the digestive tract also enables esophageal spasms and,at the pulmonary level, bronchial spasm (treatment of asthma), to beremoved. This modulation of ionized calcium may also be useful asadjuvant in the treatment of cancer and that of hypercoagulation.

Moreover, the present description is not limiting; in fact, thefundamental investigations emphasize the primary role played by calciumin many physiological and physiopathological phenomena.

Pharmacological trials in dogs and rats have proved, in vivo, that theactivity of the compounds of the invention is at least equal to that ofother known 1,4-dihydropyridine compounds, but that they are endowedwith a longer-lasting action and confirm their value in therapeuticaluse. In fact, the different 1,4-dihydropyridine compounds known untilnow have a short-term activity, which constitutes a considerabledisadvantage in human and animal therapeutics.

The invention also extends to pharmaceutical compositions containing, asthe active principle, at least one compound of general formula I, one ofthe optical isomers thereof or one of the addition salts thereof with aninorganic or organic acid or the quaternary ammonium salts thereof, withone or more inert, non-toxic and suitable excipients.

The pharmaceutical compositions thus obtained are advantageouslypresented in various forms such as, for example, tablets, dragees,capsules, sublingual tablets or other galenical preparations suitablefor a sublingual administration, suppositories and injectable ordrinkable solutions.

The dosage may vary widely depending on the age and the weight of thepatient, the nature and the severity of the condition as well as onwhether the administration is through the oral or the parenteral route.In general, the unit dose will range between 0.05 and 50 mg and thedaily dose, when administered orally, which can be used in human oranimal therapeutics, between 0.05 and 100 mg.

The following examples, given in a non-limiting way, illustrate theinvention.

The melting points mentioned are determined according to themicro-Kofler technique.

The proton nuclear magnetic resonance (N.M.R.) spectra were recorded at60 MHz or 200 MHz.

EXAMPLE 1(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-pentafluorophenyl-1,4-dihydropyridinehemifumarate Stage A: 10-phthalimido-3-oxo-5,8-dioxadecanoic acid ethylester

77 g of 2-[2-(phthalimido)ethoxy]ethanol are added, in portions, to asuspension of 31 g of sodium hydride in 400 ml of tetrahydrofuran, whilemaintaining the temperature in the vicinity of 25° C. The mixture isstirred for one hour and 53.6 g of ethyl chloroacetoacetate are thenadded, while maintaining the temperature of the mixture at -20° C. Themixture is allowed to stand overnight at ambient temperature and thenhydrolyzed with 1 l of 1N hydrochloric acid. Decantation, followed byextraction with ether are carried out and the organic phases arecombined. The combined organic phase is washed with water and then driedover magnesium sulfate. It is concentrated and the residue therebyobtained (110 g) is purified by silica column chromatography using adichloromethane:acetone (95:5) mixture as the eluting solvent. Afterremoving the eluting solvent, 35.7 g of10-phthalimido-3-oxo-5,8-dioxadecanoic acid ethyl ester are obtained.

Yield: 30%

Elemental analysis:

    ______________________________________                                                   C          H      N                                                ______________________________________                                        Theoretical (%)                                                                            59.49        5.82   3.85                                         Found (%)    59.28        5.78   3.93                                         ______________________________________                                    

Stage B:(4R,S)-3-Ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-pentafluorophenyl-2-{[2-(2-phthalimidoethoxy)ethoxy]-methyl}-1,4-dihydropyridine

10.8 g of pentafluorobenzaldehyde are added into a solution of 105 ml ofisopropanol containing 20 g of the10-phthalimido-3-oxo-5,8-dioxadecanoic acid ethyl ester previouslyobtained and 6.30 g of methyl 2-aminocrotonate.

The mixture is heated under reflux overnight and then evaporated underreduced pressure so as to obtain 39 g of a thick oil. Purification iscarried out by silica column chromatography, using acyclohexane:ethylacetate (80:20) mixture as the eluting solvent. Afterevaporating off the eluting solvent, recrystallization is carried outtwice in methanol so as to obtain 2.3 g of(4R,S)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-pentafluorophenyl-2-{[2-(2-phthalimido-ethoxy)ethoxy]methyl}1,4-dihydropyridine.

Yield: 6%

Melting point: 143°-144° C.

Elemental analysis:

    ______________________________________                                                   C          H      N                                                ______________________________________                                        Theoretical (%)                                                                            56.43        4.26   4.38                                         Found (%)    56.46        4.23   4.28                                         ______________________________________                                    

Stage C

6.8 g of the compound obtained in the previous stage are dissolved in 68ml of ethanol containing 2.3 ml of hydrazine hydrate. The mixture isheated under reflux, with stirring, for three hours and then filtered.The filtrate is collected and then evaporated. The residue obtained isdissolved in ethyl ether, filtered and extracted with a 1N sulfuric acidsolution. The aqueous phase is made alkaline using concentrated sodiumhydroxide and then extracted with ethyl ether. The extract is evaporatedto dryness. After recrystallizing the residue in isopropyl ether, 2.3 gof(4R,S)-2-{[2-(2-aminoethoxy)ethoxy]methyl}-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-pentafluorophenyl-1,4-dihydropyridineare obtained.

Yield: 35%

Melting point: 72°-73° C.

In order to prepare the(4R,S)-2-{[2-(2-aminoethoxy)ethoxy]methyl}-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-pentafluorophenyl-1,4-dihydropyridinehemifumarate, the quantity of base obtained above is dissolved in a 2%0.00226M fumaric acid solution. The mixture is heated under reflux inethanol and then evaporated to dryness and recrystallized in ethanol.

Melting point: 146°-148° C.

Elemental analysis:

    ______________________________________                                                   C          H      N                                                ______________________________________                                        Theoretical (%)                                                                            50.89        4.81   4.95                                         Found (%)    50.91        4.80   4.80                                         ______________________________________                                    

The spectral physical constants of(4R,S)-2-{[2-(2-aminoethoxy)ethoxy]methyl}-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-pentafluorophenyl-1,4-dihydropyridinehemifumarate are given in Table I.

EXAMPLE 2(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-(2,3-methylenedioxyphenyl)-1,4-dihydropyridine

This compound was prepared according to the process described in Example1, but replacing the pentafluorobenzaldehyde in stage B with2,3-methylenedioxybenzaldehyde.

Overall yield: 15.5%

Melting point: 98°-100° C.

Elemental analysis:

    ______________________________________                                                   C          H      N                                                ______________________________________                                        Theoretical (%)                                                                            59.73        6.54   6.06                                         Found (%)    59.49        6.41   5.91                                         ______________________________________                                    

The spectral physical constants are given in Table I.

EXAMPLE 3(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-(2,3,4-trimethoxyphenyl)-1,4-dihydropyridinefumarate

This compound was also prepared according to the process described inExample 1, but replacing the pentafluorobenzaldehyde in stage B with2,3,4-trimethoxybenzaldehyde.

Overall yield: 8.4%

Melting point: 130° C.

Elemental analysis:

    ______________________________________                                                   C          H      N                                                ______________________________________                                        Theoretical (%)                                                                            55.76        6.45   4.48                                         Found (%)    55.83        6.60   4.81                                         ______________________________________                                    

The spectral physical constants of the corresponding base are given inTable I.

EXAMPLE 4(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2-chlorophenyl)-3-(2,2-dicyclopropylethoxycarbonyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinefumarate Stage A: 2,2-Dicyclopropylethyl ester of10-phthalimido-3-oxo-5,8-dioxadecanoic acid

A mixture of approximately 29.5 g of 8-phthalimido-3,6-dioxaoctanoicacid and 155 ml of thionyl chloride is heated under reflux until gasevolution ceases. After cooling, the excess thionyl chloride is removedby distillation and the 31.1 g of acid chloride thus obtained are takenup with benzene. The solvent is evaporated off and the residue isdissolved in 10 ml of methylene chloride. This solution is introduceddropwise into a mixture consisting of 13.6 g of Meldrum's acid, 15.3 mlof pyridine and 75 ml of methylene chloride, while maintaining thetemperature between 0° and 5° C. The mixture is allowed to stand for 3hours at ambient temperature and then diluted with 300 ml of methylenechloride, washed with 100 ml of 1N hydrochloric acid and then with asaturated sodium bicarbonate solution, rinsed with water and dried overanhydrous magnesium sulfate. The organic solvent is evaporated off andthe evaporation residue is dissolved in 48 g of 2,2-cyclopropylethanol.A few mg of malonic acid are added and the mixture is heated at 145° C.for approximately 5 hours. The excess 2,2-dicyclopropylethanol is thenremoved by distillation, the residue is taken up with dichloromethaneand the solution is washed with a saturated sodium bicarbonate solutionand then with water, dried over anhydrous magnesium sulfate and theorganic solvent is evaporated off.

The oil obtained after evaporation is purified by silica columnchromatography, using a dichloromethane:ethyl acetate (95:5) mixture asthe eluting solvent.

5.7 g of 2,2-dicyclopropylethyl ester of10-phthalimido-3-oxo-5,8-dioxadecanoic acid are obtained.

Yield: 12.5%

Elemental analysis:

    ______________________________________                                                   C          H      N                                                ______________________________________                                        Theoretical (%)                                                                            65.00        56.59  316                                          Found (%)    64.76        6.50   3.10                                         ______________________________________                                    

Proton nuclear magnetic resonance spectrum (CDCl₃): 0.0-0.9 ppm, m, 11H;3.5 ppm, s, 2H; 3.7 ppm, s, 4H; 3.7-4.0 ppm, m, 4H; 4.0-4.4 ppm, m, 2H;4.2 ppm, s, 2H; 7.6-8.2 ppm, m, 4H.

Stage B

The(4R,S)-2-{[2-(2-aminoethoxy)ethoxy]methyl}-4-(2-chlorophenyl)-3-(2,2-dicyclopropylethoxycarbonyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinefumarate is obtained by reacting the ester prepared in stage A with2-chlorobenzaldehyde and methyl 2-a inocrotonate according to theprocess described in stages B and C of Example 1.

Yield: 10%

Melting point: 198°-199° C.

Mass spectrum of the base (chemical ionization with NH₃); 533 m/_(z) (M⁺+1), 430 m/_(z), 428 m/_(z), 106 m/_(z).

EXAMPLE 5(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinefumarate

This compound was prepared according to the process described in Example1, but replacing the pentafluorobenzaldehyde with 2-chlorobenzaldehyde.

Yield: 10%

Melting point: 188°-190° C.

Elemental analysis:

    ______________________________________                                                   C    H          N      Cl                                          ______________________________________                                        Theoretical (%)                                                                            54.88  5.84       4.92 6.23                                      Found (%)    54.61  5.92       4.86 6.34                                      ______________________________________                                    

The spectral physical constants of the corresponding base are given inTable I.

EXAMPLE 6(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridineStage A: 10-phthalimido-3-oxo-5,8-dioxadecanoic acid ethyl ester

77 g of 2-[2-(phthalimido)ethoxy]ethanol are added, in portions, to asuspension of 31 g of sodium hydride in 400 ml of tetrahydrofuran, whilemaintaining the temperature in the vicinity of 25° C. The mixture isstirred for one hour and 53.6 g of ethyl chloroacetoacetate are thenadded, while maintaining the temperature of the mixture at -20° C. Themixture is allowed to stand overnight at ambient temperature and thenhydrolyzed with 1 l of 1N hydrochloric acid. Decantation, followed byextraction with ether are carried out and the organic phases arecombined. The combined organic phase is washed with water and then driedover magnesium sulfate. It is concentrated and the residue therebyobtained (110 g) is purified by silica column chromatography using adichloromethane:acetone (95:5) mixture as the eluting solvent.

After removing the eluting solvent, 35.7 g of10-phthalimido-3-oxo-5,8-dioxadecanoic acid ethyl ester are obtained.

Yield: 30%

Elemental analysis:

    ______________________________________                                                   C          H      N                                                ______________________________________                                        Theoretical (%)                                                                            59.49        5.82   3.85                                         Found (%)    59.28        5.78   3.93                                         ______________________________________                                    

Stage B:(4R,S)-4-(2,3-Dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-{[2-(2-phtalimidoethoxy)ethoxy]-methyl}-1,4-dihydropyridine

9.7 g of 2,3-dichlorobenzaldehyde are added into a solution of 110 ml ofisopropanol containing 20 g of the 10-phtalimido-3-oxo-5,8-dioxadecanoicacid ethyl ester previously obtained and 6.40 g of methyl2-aminocrotonate.

The mixture is heated under reflux overnight and the evaporated underreduced pressure so as to obtain a thick oil. Purification is carriedout by silica column chromatography, using a cyclohexane: ethylacetate(70:30) mixture as the eluting solvent. After evaporating off theeluting solvent, recrystallization is carried out twice in methanol soas to obtain 12.2 g of(4R,S)-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-{[2-(2-phtalimidoethoxy)ethoxy]methyl}-1,4-dihydropyridine.

Yield: 36%

Stage C

12 g of the compound obtained in the previous stage are dissolved in 120ml of ethanol containing 2.9 ml of hydrazine hydrate. The mixture isheated under reflux, with stirring, for three hours and then filtered.The filtrate is collected and then evaporated. The residue obtained isdissolved in ethyl ether, filtered and extracted with a 1N hydrochloricacid solution. The aqueous phase is made alkaline using concentratedsodium hydroxide and then extracted with ethyl ether. The extract isevaporated to dryness.

Yield: 48%

Melting point: 77°-79° C.

Elemental analysis:

    ______________________________________                                                   C    H          N      Cl                                          ______________________________________                                        Theoretical (%)                                                                            54.21  5.79       5.74 14/54                                     Found (%)    54.32  5.74       5.72 14.67                                     ______________________________________                                    

The spectral physical constants thereof are given in Table I.

EXAMPLE 7(4R,S)-2-[{2-[2-(N-Methyl-N-benzylamino)ethoxy]ethoxy}-methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinetartrate Stage A: 10-[(N-Methyl-N-benzyl)amino]-3-oxo-5,8-dioxadecanoicacid ethyl ester

In order to prepare this compound, the procedure described in Example 1(Stage A) is used, but the 2-(2-phtalimidoethoxy)ethanol is replacedwith 2-[2-(N-methyl-N-benzylamino)ethoxy]ethanol.

Yield: 6.8%

Proton nuclear magnetic resonance spectrum (CDCl₃): 1.3 ppm, t, 3H; 2.3ppm, s, 3H; 2.6 ppm, t, 2H, 3.4-3.7 ppm, m, 10H; 4.2 ppm, s, 2H; 4.2ppm, m, 2H; 7.4 ppm, s, 5H.

Stage B:(4R,S)-2-[{2-[2-(N-Methyl-N-benzylamino)ethoxy]ethoxy}methyl]-3-ethoxycarbonyl-4-(2-chlorophenyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine

This base is obtained according to the method described in Example 1(stage B), but replacing the pentafluorobenzaldehyde with2-chlorobenzaldehyde and also replacing the10-phthalimido-3-oxo-5,8-dioxadecanoic acid ethyl ester with the esterobtained in stage A above.

Yield: 40%

The spectral physical constants of this base are given in Table I.

When subjected to the action of tartaric acid, the base described aboveis converted into tartrate.

Elemental analysis:

    ______________________________________                                                   C    H          N      Cl                                          ______________________________________                                        Theoretical (%)                                                                            57.74  6.08       3.96 5.01                                      Found (%)    58.04  6.04       3.84 5.04                                      ______________________________________                                    

EXAMPLE 8(4R,S)-4-(2-Chlorophenyl)-2-[{2-[2-(N,N-diallylamino)ethoxy]ethoxy}methyl]-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinehemifumarate

4.5 g of the compound of Example 5 and 1.92 g of allyl bromide aredissolved in 40 ml of acetonitrile, in the presence of 0.0086M of drypotassium carbonate. The mixture is heated under reflux for 16 hours andthe precipitate is then filtered, the solvent is evaporated off and theresidue is taken up with dichloromethane; the solution is washed withwater and evaporated. The residue is chromatographed on a silica column,using a dichloromethane:ethyl acetate (50:50) mixture as eluant so as toobtain pure(4R,S)-4-(2-chlorophenyl)-2-[{2-[2-(N,N-diallylamino)ethoxy]ethoxy}methyl]-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine(0.7 g).

Yield: 13%

The spectral physical constants of this compound are given in Table I.

The 0.7 g of the compound obtained above is subjected to the action offumaric acid so as to obtain, after recrystallization in ethanol, 0.4 gof the corresponding hemifumarate.

Melting point: 126°-128° C.

Elemental analysis:

    ______________________________________                                                   C    H          N      Cl                                          ______________________________________                                        Theoretical (%)                                                                            60.96  6.65       4.74 6.00                                      Found (%)    60.94  6.57       4.71 5.96                                      ______________________________________                                    

EXAMPLE 9(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2-chlorophenyl)-5-(2,2-dicyclopropylethoxycarbonyl)-3-ethoxycarbonyl-6-methyl-1,4-dihydropyridinefumarate

The corresponding base is obtained according to the process described inExample 1, but replacing the pentafluorobenzaldehyde with2-chlorobenzaldehyde and the methyl 2-aminocrotonate with2,2-dicyclopropylethyl 2-aminocrotonate.

Overall yield: 19%

The spectral physical constants for(4R,S)-2-{[2-(2-aminoethoxy)ethoxy]methyl}-4-(2-chlorophenyl)-5-(2,2-dicyclopropylethoxycarbonyl)-3-ethoxycarbonyl-6-methyl-1,4-dihydropyridineare given in Table I.

3.9 g of this base are dissolved in a 2% solution of fumaric acid inethanol. The precipitate obtained is recrystallized in methanol so as toobtain 2.7 g of the expected salt.

Melting point: 166°-168° C.

Elemental analysis:

    ______________________________________                                                   C    H          N      Cl                                          ______________________________________                                        Theoretical (%)                                                                            59.76  6.53       4.22 5.34                                      Found (%)    59.75  6.80       4.15 5.44                                      ______________________________________                                    

EXAMPLE 10(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methoxymethyl-1,4-dihydropyridineStage A: 2-(2,3-Dichlorobenzylidene)-3-oxo-4-methoxybutanoic acid methylester

A solution containing 160 ml of anhydrous benzene, 5 g of2,3-dichlorobenzaldehyde, 4.2 g of 4-methoxy-3-oxobutanoic acid methylester, 16 drops of pyridine and 22 drops of hexanoic acid is heatedunder reflux for one hour, removing the water formed. The mixture isthen washed with a saturated sodium bicarbonate solution and then with a0.1N hydrochloric acid solution. The organic phase is taken andevaporated to dryness so as to obtain 8.3 g of an oil.

Yield: 96.5%

Proton nuclear magnetic resonance spectrum (CDCl₃): 3.3-3.4 ppm, d, 3H;3.7-3.9 ppm, d, 3H; 4.0-4.3 ppm, d, 2H; 7.0-7.7 ppm, m, 3H; 8 ppm, d,1H.

Stage B:(4R,S)-2-{[2-(2-Phthalimidoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methoxymethyl-1,4-dihydropyridine

8.2 g of the ester from stage A of Example 1, 1.7 g of ammonium acetateand 10 ml of ethanol are heated under reflux for 20 minutes. A solutionconsisting of 8.2 g of the methyl ester obtained in stage A above and 5ml of ethanol is then added into the reaction medium. The reactionmedium is heated at boiling point for two and a half hours. Afterevaporation, the residue is taken up with methylene chloride and washedwith bicarbonate and then with water. The solution is evaporated todryness and the oil thereby obtained is purified on a silica columnusing a cyclohexane:ethyl acetate (70:30) mixture as the eluant. Afterevaporating off the eluting solvent, 2.7 g of the expected product areobtained.

Yield: 19%

Melting point: 138°-140° C.

Stage C

The process described in stage C of Example 1 is applied to the compoundobtained above so as to obtain, after two recrystallizations inisopropyl ether,(4R,S)-2-{[2-(2-aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methoxymethyl-1,4-dihydropyridine.

Yield: 35%

Melting point: 78°-83° C.

The spectral physical constants are given in Table I.

Elemental analysis:

    ______________________________________                                                   C    H          N      Cl                                          ______________________________________                                        Theoretical (%)                                                                            53.39  5.84       5.41 13.70                                     Found (%)    52.88  5.69       5.13 14.32                                     ______________________________________                                    

EXAMPLE 11N-Benzyl-7-[(4R,S)-3-ethoxycarbonyl-4-(2,3-dichlorophenyl)-5-methoxycarbonyl-6-methyl-2-(1,4-dihydropyridyl)]-N,N-dimethyl-3,6-dioxaheptanammoniumiodide Stage A:(4R,S)-2-[{2-[2-(N-Benzylamino)ethoxy]ethoxy}-methyl]-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine

A mixture consisting of 3.7 g of the compound from Example 6, 0.8 g ofbenzaldehyde and 10 ml of anhydrous benzene is heated under reflux,removing the water with a suitable apparatus (azeotropic removal waterextractor). The organic mixture is evaporated to dryness; the residue istaken up with anhydrous ethanol and 0.3 g of sodium borohydride is addedin portions, with intermittent cooling using a cold water bath. Themixture is allowed to stand for 10 minutes with stirring, hydrolysis iscarried out on ice, followed by extraction with ethyl ether and thenwith ethyl acetate so as to obtain 3.2 g of(4R,S)-2-[{2-[2-(N-benzylamino)ethoxy]ethoxy}methyl]-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine.

Stage B

3.9 g of the product above are taken up with 9 ml of dichloromethane inthe presence of 1.1 ml of 40% sodium hydroxide and 1.3 ml of methyliodide. The mixture is allowed to stand overnight, with stirring. Thecrystals obtained are filtered and then washed with ice-cold water so asto obtainN-benzyl-7-[(4R,S)-3-ethoxycarbonyl-4-(2,3-dichlorophenyl)-5-methoxycarbonyl-6-methyl-2-(1,4-dihydropyridyl)]-N,N-dimethyl-3,6-dioxaheptanammoniumiodide.

Yield: 56.8%

Elemental analysis:

    ______________________________________                                                  C      H      N        Cl   I                                       ______________________________________                                        Theoretical (%)                                                                           50.76    3.82   3.82   9.67 17.30                                 Found (%)   50.44    5.31   3.62   9.35 17.18                                 ______________________________________                                    

The spectral physical constants of this compound are given in Table I.

EXAMPLE 12(4R,S)-2-(7-Aminoheptyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinefumarate Stage A: 10-Phthalimido-3-oxo-decanoic acid ethyl ester

10 g of oxalyl chloride are added to a solution consisting of 10.5 g of8-phthalimidooctanoic acid, 40 ml of anhydrous benzene and 0.2 ml ofpyridine. The mixture is heated under reflux for 15 minutes. The solventis evaporated off, the residue is taken up twice with benzene and anoily compound is separated after filtration. 3.0 g of the acid chloridethus obtained are added to a mixture, which has previously been cooledto 0° C., containing 1.3 g of Meldrum's acid, 1.45 g of pyridine and 8ml of dichloromethane, while maintaining the temperature at 0° C. Themixture is allowed to stand overnight at ambient temperature, taken upwith dichloromethane, washed with 10 ml of 1N hydrochloric acid, driedover anhydrous magnesium sulfate and then evaporated to dryness. Theresidue is taken up with 2.3 ml of ethanol and the mixture is heatedunder reflux until gas evolution ceases. After evaporating off thesolvent, 2.5 g of 10-phthalimido- 3-oxo-decanoic acid ethyl estercrystals are obtained.

Yield: 77%

Elemental analysis:

    ______________________________________                                                   C          H      N                                                ______________________________________                                        Theoretical (%)                                                                            66.85        9.96   3.90                                         Found (%)    66.98        6.69   4.01                                         ______________________________________                                    

Stage B:(4R,S)-4-(2-Chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-(7-phthalimidoheptyl)-1,4-dihydropyridine

This compound was prepared starting with the ester obtained in theprevious stage, using the preparation process described in Example 1stage B, but replacing the pentafluorobenzaldehyde with2-chlorobenzaldehyde.

Stage C

The(4R,S)-2-(7-aminoheptyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinewas obtained according to the procedure described in Example 1 stage C.

The spectral physical constants are given in Table I.

This compound is then dissolved in a 2% fumaric acid solution. Thesolution is evaporated to dryness, the residue is dissolved inacetonitrile and evaporated again. The fumarate obtained isrecrystallized in isopropanol.

Yield: 28%

Melting point: 135° C.

Elemental analysis:

    ______________________________________                                                  C     H          N      Cl                                          ______________________________________                                        Theoretical (%)                                                                            59.51  6.60       4.95 6.27                                      Found (%)    59.28  6.79       4.63 5.90                                      ______________________________________                                    

EXAMPLE 13(4R,S)-2-(7-Aminoheptyl)-4-(2-chlorophenyl)-3-(2,2-dicyclopropylethoxycarbonyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinefumerate

This compound is obtained according to the method described in Example12, but replacing the 10-phthalimido-3-oxodecanoic acid ethyl ester withthe 2,2-dicyclopropylethyl ester of 10-phthalimido-3-oxodecanoic acid.

Yield: 12%

Melting point: 105°-108° C.

The spectral physical constants of(4R,S)-2-(7-aminoheptyl)-3-(2,2-dicyclopropylethoxycarbonyl)-4-(2-chlorophenyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridineare given in Table I.

In order to obtain the corresponding fumarate, salification is carriedout with a 2% solution of fumaric acid in ethanol followed bycrystallization in acetonitrile.

Melting point: 137°-140° C.

Elemental analysis:

    ______________________________________                                                   C    H          N      Cl                                          ______________________________________                                        Theoretical (%)                                                                            63.29  7.03       4.34 5.49                                      Found (%)    62.67  6.91       4.45 5.05                                      ______________________________________                                    

EXAMPLE 14(4R,S)-2-(5-Aminopentyl)-4-(2-chlorphenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinecitrate Stage A: 8-Phthalimido-3-oxooctanoic acid ethyl ester

This ester is synthesized according to the process described in stage Aof Example 4, but replacing the 8-phthalimido-3,6-dioxaoctanoic acidwith 6-phthalimidohexanoic acid and the 2,2-dicyclopropylethanol withethanol.

Stage B and C

The(4R,S)-2-(5-aminopentyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridineis obtained according to the processes described in stages B and C ofExample 1, but replacing the pentafluorobenzaldehyde in stage B with2-chlorobenzaldehyde.

Yield: 65%

The spectral physical constants thereof are given in Table I.

In order to obtain the citrate, the base obtained is freeze-dried in thepresence of a 0.1N aqueous citric acid solution.

Elemental analysis:

    ______________________________________                                                   C    H          N      Cl                                          ______________________________________                                        Theoretical (%)                                                                            54.85  6.08       4.57 5.78                                      Found (%)    54.85  5.97       4.54 6.11                                      ______________________________________                                    

EXAMPLE 15(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-3,5-diethoxycarbonyl-6-methyl-4-pentafluorophenyl-1,4-dihydropyridine

This compound was prepared according to the process described in Example1, but using ethyl 2-aminocrotonate instead of its methylated homolog instage B.

Overall yield: 9%

Melting point: 69°-70° C.

Elemental analysis:

    ______________________________________                                                   C          H      N                                                ______________________________________                                        Theoretical (%)                                                                            52.87        5.20    5.36                                        Found (%)    52.71        5.18    5.10                                        ______________________________________                                    

The spectral physical constants of this compound are given in Table I.

EXAMPLE 16(4R,S)-3,5-Diethoxycarbonyl-6-methyl-4-pentafluorophenyl-2-[{2-[2-(N-propylamino)ethoxy]ethoxy}methyl]-1,4-dihydropyridineoxalate Stage A:(4R,S)-2-[{2-[2-(N-Benzylamino)ethoxy]ethoxy}methyl]-3,5-diethoxycarbonyl-6-methyl-4-pentafluorophenyl-1,4-dihydropyridine

This compound was prepared according to the process described in Example11, stage A, but using the compound from Example 15 instead of(4R,S)-2-{[2-(2-aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine.

Stage B:(4R,S)-2-[{2-[2-(N-Benzyl-N-allylamino)ethoxy]-ethoxy}methyl]-3,5-diethoxycarbonyl-6-methyl-4-pentafluorophenyl-1,4-dihydropyridine

A mixture containing 1.6 g of the compound obtained in the previousstage, 0.31 g of allylbromide and 0.18 g of potassium carbonate in 20 mlof acetonitrile is heated under reflux, with stirring, overnight. Afterevaporating off the solvent, the residue is taken up with ether,extracted exhaustively with 0.1N hydrochloric acid, made alkaline in thecold state and then extracted with ethyl acetate so as to obtain, afterevaporation, an oil corresponding to the expected structure.

Stage C

0.9 g of the compound obtained above, 0.125 g of oxalic acid and 0.3 gof palladium hydroxide, dissolved in 50 ml of methanol, are subjected toa catalytic hydrogenation at ambient temperature and at atmosphericpressure. After filtering the catalyst, 0.5 g of the expected salt isobtained.

Yield: 54%

Melting point: 151°-153° C.

The spectral physical constants of this salt are given in Table I.

EXAMPLE 17(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridinefumarate

This compound was prepared according to the process described in Example1, stage B and stage C, but using 2-trifluoromethylbenzaldehyde insteadof pentafluorobenzaldehyde in stage B.

Yield: 9%

Melting point: 176°-178° C.

Elemental analysis:

    ______________________________________                                                   C          H      N                                                ______________________________________                                        Theoretical (%)                                                                            53.82        5.52   4.64                                         Found (%)    53.72        5.53   4.56                                         ______________________________________                                    

The spectral physical constants of the corresponding base are given inTable I.

EXAMPLE 18(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(3-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinetartrate

This compound was prepared according to the process in Example 1, stagesB and C, but replacing the pentafluorobenzaldehyde with3-chlorobenzaldehyde (stage B) and, in the salification stage (stage C),the fumaric acid with tartaric acid.

Yield: 9.5%

Melting point: 118°-124° C.

The spectral physical constants of this salt are given in Table I.

EXAMPLE 19(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-3,5-dimethoxycarbonyl-6-methyl-4-pentafluorophenyldihydropyridinetartrate

This compound was prepared according to the process described in Example1 (stages B and C), but using 10-phthalimido-3-oxo-5,6-dioxadecanoicacid methyl ester instead of the ethyl ester in stage B and usingtartaric acid instead of fumaric acid for the salification.

Yield: 15%

Melting point: 187°-189° C.

Elemental analysis:

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        Theoretical (%)                                                                            46.59       4.53   4.34                                          Found (%)    46.52       4.73   4.29                                          ______________________________________                                    

The spectral physical constants of(4R,S)-2-{[2-(2-aminoethoxy)ethoxy]methyl}-3,5-dimethoxycarbonyl-6-methyl-4-pentafluorophenyldihydropyridineare given in Table I.

EXAMPLE 20(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-5-ethoxycarbonyl-3-methoxycarbonyl-6-methyl-4-pentafluorophenyldihydropyridinetartrate

This compound was also prepared according to the process described inExample 1, but using ethylcrotonate instead of methylcrotonate in stageB.

Yield: 6%

Melting point: 190°-192° C.

Elemental analysis:

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        Theoretical (%)                                                                            47.42       4.74   4.25                                          Found (%)    47.75       4.83   4.25                                          ______________________________________                                    

The spectral physical constants of the corresponding base are given inTable I.

EXAMPLE 21(4R,S)-2-[{2-[2-(N-Trifluoroacetylamino)ethoxy]-ethoxy}methyl]-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-pentafluorophenyl-1,4-dihydropyridine

In order to obtain this compound, the compound from Example 1 issubjected to the action of triethylamine and trifluoroacetic acid ethylester in methanol, at ambient temperature for approximately 48 hours.After filtering the precipitate formed, it is washed with ice-coldmethanol (14° C.) and the expected product is obtained in the purestate.

Melting point: 148°-150° C.

Elemental analysis:

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        Theoretical (%)                                                                            47.69       4.00   4.63                                          Found (%)    47.66       4.30   4.59                                          ______________________________________                                    

The spectral physical constants of this base are given in Table I.

EXAMPLE 22(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-3-ethoxycarbonyl-5-methoxycarbonyl-4-(2-methoxy-3-methyl-thiophenyl)-1,4-dihydropyridinefumarate

This compound was obtained with the synthetic process described inExample 1 (stages B and C), but using 2-methoxy-3-methylthiobenzaldehydeinstead of pentafluorobenzaldehyde.

The preparation of the former substance is known (Bull. Soc. Chim. ofJapan (1978), 51, (8), p. 2435-2436).

Yield: 13.5%

Melting point: 120° C.

Elemental analysis:

    ______________________________________                                                   C    H          N      S                                           ______________________________________                                        Theoretical (%)                                                                            55.07  6.27       4.59 5.25                                      Found (%)    55.11  6.14       4.42 5.32                                      ______________________________________                                    

The spectral physical constants of this salt are given in Table I.

EXAMPLE 23(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-3-(4-nitrobenzyloxycarbonyl)-5-methoxy-6-methyl-4-pentafluorophenyl-1,4-dihydropyridinetartrate Stage A: 4-Nitrobenzyl ester of10-phthalimido-3-oxo-5,8-dioxadecanoic acid

35 g of 8-phthalimido-3-6-dioxaoctanoic acid with 18 g ofcarbonyldiimidazol in 750 ml of a mixture of dimethylformamide andacetonitrile (3:1) are allowed to stand overnight, under nitrogen. 34 gof magnesium 2-(4-nitrobenzyloxycarbonyl)acetate are then added and leftto remain in contact for 18 hours. After evaporating off the reactionsolvent, the residue is taken up with dichloromethane and washed withwater. The residue is then purified on a silica gel column, using adichloromethane: acetone (95:5) mixture as the eluant, so as to give theexpected compound.

Yield: 32.8%

Proton nuclear magnetic resonance spectrum (CDCl₃): 3.6 ppm, s, 6H;3.7-4 ppm, m, 4H; 4.2 ppm, s, 2H; 5.3 ppm, s, 2H; 7.8 ppm, m, 4H; 7.6ppm, d, 2H; 8.3 ppm, d, 2H.

Stage B

The2-{[2-(2-aminoethoxy)ethoxy]methyl}-3-(4-nitrobenzyloxycarbonyl)-5-methoxy-6-methyl-4-pentafluorophenyldihydropyridinewas prepared according to the process described in Example 1, stages Band C, condensing the compound obtained in the previous stage withpentafluorobenzaldehyde. The spectral physical constants thereof aregiven in Table I.

Yield: 50%

Elemental analysis:

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        Theoretical (%)                                                                            47.81       4.27   5.57                                          Found (%)    48.04       4.19   5.29                                          ______________________________________                                    

The corresponding salt was obtained after adding a sufficient quantityof tartaric acid dissolved in ethanol.

Melting point: 152°-154° C.

EXAMPLE 24(4R,S)-2-{[3-(3-Aminopropoxy)propoxy]methyl}-3-ethoxycarbonyl-5-methoxycarbonyl-4-pentafluorophenyl-1,4-dihydropyridinetartrate Stage A: 12-Phthalimido-3-oxo-5,9-dioxadodecanoic acid ethylester

This compound was prepared according to the process described in stage Aof Example 1, but using 3-(3-phthalimidopropoxy)propanol.

Proton nuclear magnetic resonance spectrum (CDCl₃): 1.3 ppm, t, 3H;1.6-2.2 ppm, m, 4H; 3.3-4.0 ppm, m, 10H; 4.1 ppm, s, 2H: 4.2 ppm, q, 2H;7.7-8.3 ppm, m, 4H.

Stage B

The2-{[3-(3-aminopropoxy)propoxy]methyl}-3-ethoxycarbonyl-5-methoxycarbonyl-4-pentafluorophenyl-1,4-dihydropyridinewas prepared according to the process described in Example 1, stages Band C, using the compound obtained above.

The spectral physical constants thereof are given in Table I.

The corresponding tartrate was formed after adding a sufficient quantityof tartaric acid.

Yield: 11%

Melting point: 104° C.

Elemental analysis:

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        Theoretical (%)                                                                            48.98       5.14   4.08                                          Found (%)    48.73       5.12   4.08                                          ______________________________________                                    

EXAMPLE 25(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-isopropoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinefumarate Stage A: 10-Phthalimido-3-oxo-5,8-dioxadecanoic acid isopropylester

This compound was prepared according to the process described in Example4, stage A, but using isopropyl alcohol instead of2,2-dicyclopropylethanol.

Yield: 67%

Proton nuclear magnetic resonance spectrum (CDCl₃): 1.3 ppm, d, 6H; 3.5ppm, s, 2H, 3.7 ppm, s, 4H; 3.7-4.2 ppm, m, 4H; 4.2 ppm, s, 2H; 4.8-5.4ppm, m, 1H; 7.6-8.2 ppm, m, 4H.

Stage B

The(4R,S)-2-{[2-(2-aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-isopropoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinewas prepared starting with the compound obtained in the previous stageand with 2,3-dichlorobenzaldehyde according to the process described inExample 1, stages B and C. The spectral physical constants thereof aregiven in Table I.

Yield: 17.5%

This base was then salified with fumaric acid so as to form thecorresponding salt.

Melting point: 106° C. (decomposition)

Elemental analysis:

    ______________________________________                                                   C    H          N      Cl                                          ______________________________________                                        Theoretical (%)                                                                            51.58  5.66       4.63 11.71                                     Found (%)    51.47  5.39       4.40 11.74                                     ______________________________________                                    

EXAMPLE 26(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-3-isopropoxycarbonyl-5-methoxycarbonyl-6-methyl-4-pentafluorophenyl-1,4-dihydropyridinetartrate

The corresponding base was prepared according to the process describedin the previous example, but using pentafluorobenzaldehyde instead of2,3-dichlorobenzaldehyde.

Yield: 9%

Melting point: 56.9° C.

The(4R,S)-2-{[2-(2-aminoethoxy)ethoxy]methyl}-3-isopropoxycarbonyl-5-methoxycarbonyl-6-methyl-4-pentafluorophenyl-1,4-dihydropyridinetartrate was formed after adding a sufficient quantity of DL-tartaricacid dissolved in ethanol.

Elemental analysis:

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        Theoretical (%)                                                                            48.21       4.94   4.16                                          Found (*) (%)                                                                              47.53       5.02   4.06                                          ______________________________________                                         (*) Results corrected for 2.3% of water.                                 

The spectral physical constants of the base are given in Table I.

EXAMPLE 27(4R,S)-2-{[3-(3-Aminopropoxy)propoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinefumarate

This compound was prepared according to the process described in Example24, but using 2,3-dichlorobenzaldehyde instead ofpentafluorobenzaldehyde, and a 2% solution of fumaric acid in ethanolinstead of tartaric acid for the salification. The spectral physicalconstants of the base are given in Table I.

Yield: 25%

Melting point: 131°-133° C.

Elemental analysis:

    ______________________________________                                                   C    H          N      Cl                                          ______________________________________                                        Theoretical (%)                                                                            53.25  5.74       4.43 11.22                                     Found (%)    53.19  5.77       4.45 11.23                                     ______________________________________                                    

EXAMPLE 28(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-isobutyloxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinefumarate Stage A: 10-Phthalimido-3-oxo-5,8-dioxadecanoic acid isobutylester

This compound was prepared according to the process described in Example4, stage A, but using isobutyl alcohol instead of2,2-dicyclopropylethanol.

Yield: 55%

Proton nuclear magnetic resonance spectrum (CDCl₃): 0.9 ppm, d, 6H;1.5-2.4 ppm, m, 1H; 3.6 ppm, s, 2H; 3.5-4.2 ppm, m, 8H; 4 ppm, d, 2H;4.2 ppm, s, 2H; 7.5-8 ppm, m, 4H.

Stage B

The(4R,S)-2-{[2-(2-aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-isobutyloxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinefumarate was prepared starting with the compound obtained in theprevious stage and according to the process described in Example 25,stage B. The spectral physical constants thereof are given in Table I.

Yield: 17%

Melting point: 130° C.

Elemental analysis:

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        Theoretical (%)                                                                            53.25       5.74   4.43                                          Found (%)    53.06       5.54   4.41                                          ______________________________________                                    

EXAMPLE 29(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-{[(E)-4,4-dicyclopropyl-2-butene]-oxycarbonyl}-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinetartrate Stage A: (E)-4,4-dicyclopropyl-3-butenoic acid ethyl ester

A mixture containing 0.383 mole of 2,2-dicyclopropylacetaldehyde and0.574 mole of (carbethoxymethylene)triphenylphosphorane in 800 ml oftoluene is heated under reflux for 24 hours. After removing theprecipitate formed, the solvent is evaporated off and the residual oilis dissolved in 1575 ml of dimethylformamide. After adding 1575 ml of 3Nsulfuric acid, the reaction medium is extracted with 3 liters of hexane.The organic phase is then dried and evaporated to dryness so as toobtain the ester expected.

Yield: 79%

Proton nuclear magnetic resonance spectrum (CDCl₃): 0.0-1.4 ppm, m, 11H;1.5 ppm, t, 3H; 6 ppm, d, 1H; 7.1 ppm, d, 1H.

Stage B: (E)-4,4-Dicyclopropyl-3-buten-1-ol

656 ml of a 1.5M solution of isobutyl aluminum hydride in toluene iscooled to 0° C. and 68.5 g of the ester obtained in the previous stageare added slowly. The mixture is allowed to stand overnight at ambienttemperature and is hydrolyzed first with 500 ml of a toluene:methanol(1:1) mixture and then with 1 l of 1N hydrochloric acid. Afterdistillation, the expected alcohol is obtained.

Yield: 75%

Proton nuclear magnetic resonance spectrum (CDCl₃): 0-1.5 ppm, m, 11H;1.5-2 ppm, m, 1H; 4.0-4.3 ppm, m, 2H; 5.6-5.9 ppm, m, 15H.

Stage C: (E)-4,4-Dicyclopropyl-2-butenyl ester of10-phthalimido-3-oxo-5,8-dioxadecanoic acid

This compound was prepared according to the process described in Example4, stage A, using the alcohol obtained in the previous stage.

Yield: 50%

Stage D

The(4R,S)-2-{[2-(2-aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-{[(E)-4,4-dichloropropyl-2-butenyl]oxycarbonyl}-5methoxycarbonyl-6-methyl-1,4-dihydropyridine was obtained using theester prepared in the previous stage and according to the processdescribed in Example 1, stages B and C.

The spectral physical constants of this base are given in Table I.

After salification with DL-tartaric acid, the corresponding tartrate isobtained in the solid form.

Yield: 18%

Melting point: 146° C.

Elemental analysis:

    ______________________________________                                                   C    H          N      Cl                                          ______________________________________                                        Theoretical (%)                                                                            54.91  5.96       3.78 9.53                                      Found (%)    54.50  5.94       3.69 9.59                                      ______________________________________                                    

EXAMPLE 30(4R,S)-2-{[3-(3-Aminopropoxy)propoxy]methyl}-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-(2-methylthio-3-trifluoromethylphenyl)-1,4-dihydropyridinefumarate Stage A: 2-Chloro-3-trifluoromethylbenzaldehyde

A solution of 0.6 mole of 2-chlorotrifluoromethylbenzene in 1 l oftetrahydrofuran is cooled to -65° C. and 0.58 mole of butyllithiumdissolved in hexane is added. The mixture is maintained at the sametemperature for 2 hours and a mixture containing 44 ml ofdimethylformamide and 200 ml of tetrahydrofuran is then added dropwise.The reaction medium is allowed to return to ambient temperature, 600 mlof water are added, extraction is then carried out with ethyl etherfollowed by evaporation to dryness. The product is distilled to purify.

Yield: 40%

Proton nuclear magnetic resonance spectrum (CDCl₃): 7.5-7.9 ppm, m, 2H;8.0-8.4 ppm, m, 2H.

Stage B: 2-Methylthio-3-trifluoromethylbenzaldehyde

0.45 mole of the aldehyde obtained in the previous stage, dissolved in250 ml of dimethylformamide, is added to a suspension containing 0.45mole of sodium-methyl sulfide. The medium is heated to 55° C., allowedto return to ambient temperature, hydrolyzed with 500 ml of water,extracted with ether, dried and distilled to obtain the expectedaldehyde.

Yield: 30%

Proton nuclear magnetic resonance spectrum (CDCl₃): 2.4 ppm, s, 3H;7.4-8.3 ppm, m, 3H; 10.9 ppm, s, 1H.

Stage C

The(4R,S)-2-{[3-(3-aminopropoxy)propoxy]methyl}-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-(2-methylthio-3-trifluoromethylphenyl)-1,4-dihydropyridinewas prepared according to the process described in Example 1, stages Band C, using the aldehyde described above. The corresponding salt wasobtained using a sufficient quantity of fumaric acid. The physicalconstants of this compound are described in Table I.

Yield: 15%

Melting point: 158° C.

Elemental analysis:

    ______________________________________                                                   C    H          N      S                                           ______________________________________                                        Theoretical (%)                                                                            53.25  5.81       4.14 4.74                                      Found (%)    52.59  5.58       3.59 4.72                                      ______________________________________                                    

EXAMPLE 31(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-(2,3,5-trichlorophenyl)-1,4-dihydropyridinefumarate

This compound was obtained according to the process described in Example1, stages B and C, using 2,3,5-trichlorobenzaldehyde and a sufficientquantity of fumaric acid.

Yield: 21%

Melting point: 114° C.

Elemental analysis:

    ______________________________________                                                   C    H          N      Cl                                          ______________________________________                                        Theoretical (%)                                                                            48.95  4.89       4.39 16.67                                     Found (%)    48.77  4.78       3.99 16.86                                     ______________________________________                                    

The spectral physical constants of the compound are given in Table I.

EXAMPLE 32(4R,S,)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-(2,3,6-trichlorophenyl)-1,4-dihydropyridinefumarate

This compound was prepared according to the process described in Example31, but using 2,3,6-trichlorobenzaldehyde instead of2,3,5-trichlorobenzaldehyde.

Melting point: 118° C.

Elemental analysis:

    ______________________________________                                                   C    H          N      Cl                                          ______________________________________                                        Theoretical (%)                                                                            48.95  4.89       4.39 16.67                                     Found (%)    48.74  4.85       4.36 17.00                                     ______________________________________                                    

The spectral physical constants of the corresponding base are describedin Table I.

EXAMPLE 33(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-(4,4-dicyclopropylbutyloxycarbonyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinefumarate Stage A: 4,4-Dicyclopropylbutanoic acid ethyl ester

0.298 mole of the ester obtained in stage A of Example 29 is dissolvedin 500 ml of ethanol and it is then subjected to a catalytichydrogenation at ambient temperature and in the presence of palladinizedcharcoal containing 5% palladium.

Yield: 94.5%

Proton nuclear magnetic resonance spectrum (CDCl₃): 1.0 ppm, m, 11H; 1.3ppm, t, 3H; 1.85 ppm, q, 2H; 2.5 ppm, t, 2H; 4.2 ppm, q, 2H.

Stage B: 4,4-Dicyclopropylbutanol

0.1 mole of the ester obtained in the previous stage, in 400 ml of ethylether, is subjected to the action of 0.1 mole of lithium aluminumhydride. Hydrolysis is carried out followed by distillation so as toobtain the expected alcohol.

Yield: 93%

Stage C: 4,4,-Dicyclopropylbutyl ester of10-phthalimido-3-oxo-5,8-dioxadecanoic acid

This compound was prepared according to the process described in Example4, stage A, but using the alcohol obtained above instead of2,2-dicyclopropylethanol.

Yield: 48%

Proton nuclear magnetic resonance spectrum (CDCl₃): 0.0-0.7 ppm, m, 10H;1.0-2.0 ppm, m, 5H; 3.5-4.3 ppm, t,+s+m, 14H; 7.6-8.1 ppm, m, 4H.

Stage D

The(4R,S)-2-{[2-(2-aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-(4,4-dicyclopropylbutyloxycarbonyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinefumarate was prepared starting with the ester described in stage C aboveand according to the process described in stages B and C of Example 1.

Yield: 20%

Melting point: 175° C.

Elemental analysis:

    ______________________________________                                                   C    H          N      Cl                                          ______________________________________                                        Theoretical (%)                                                                            57.38  6.23       3.93 9.96                                      Found (%)    57.01  6.27       3.86 9.90                                      ______________________________________                                    

The spectral physical constants of the corresponding base are given inTable I.

EXAMPLE 34(4R,S)-3-Ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-pentafluorophenyl-2-[{2-[2-(N-propylamino)ethoxy]ethoxy}-methyl]-1,4-dihydropyridinefumarate Stage A:(4R,S)-3-Ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-pentafluorophenyl-2-[{2-[2-(N-allyl-N-benzylamino)-ethoxy]ethoxy}methyl]-1,4-dihydropyridine

The(4R,S)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-pentafluorophenyl-2-[{2-[2-(N-benzylamino)ethoxy]-ethoxy}methyl]-1,4-dihydropyridinewas obtained in the form of an oil, by reacting the compound fromExample 1 with benzaldehyde according to the process described inExample 11. 0.027 mole of this compound is then heated under refluxovernight, under nitrogen, with 0.027 mole of allyl bromide and 0.0135mole of potassium carbonate in 200 ml of acetonitrile. After filtration,the reaction solvent is evaporated off, the residue is taken up withwater and ethyl ether and the ethereal phase is then exhaustivelyextracted with 1N hydrochloric acid. The aqueous phase is made alkalineand extracted with ether. The organic phases are dried and evaporated todryness to obtain the expected compound.

Yield: 57%

Proton nuclear magnetic resonance spectrum (CDCl₃): 1.0-1.3 ppm, m, 3H;2.3 ppm, s, 3H; 2.5-2.8 ppm, t, 2H; 3.0-3.2 ppm, d, 2H; 3.4-3.7 ppm,m+s, 8H+3H; 3.8-4.2 ppm, q, 2H; 4.6 ppm, s, 2H; 4.9-6.1 ppm, m+s+m,1H+1H+1H; 7.3 ppm, m, 5H; 7.6 ppm, 1H exchangeable.

Stage B

A mixture containing 0.014 mole of the compound obtained in the previousstage and 0.014 mole of oxalic acid in 500 ml of methanol, is subjectedto a catalytic hydrogenation in the presence of 3 g of palladiumhydroxide at ambient temperature and at atmospheric pressure. After themixture has been evaporated and made alkaline, the(4R,S)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-pentafluorophenyl-2-[{2-[2-(N-propylamino)ethoxy]ethoxy}methyl]-1,4-dihydropyridineis obtained, which is converted into the fumarate thereof.

Yield: 59%

Melting point: 124° C.

Elemental analysis:

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        Theoretical (%)                                                                            52.25       5.29   4.20                                          Found (%)    51.90       5.36   4.25                                          ______________________________________                                    

The spectral physical constants of the base are given in Table I.

EXAMPLE 35(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2-chloro-3-trifluoromethylphenyl)-3-isopropoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinetartrate

This compound, in the form of the base, was prepared according to theprocess described in Example 1, stages B and C, using the2-chloro-3-trifluoromethyl benzaldehyde described in Example 30, stageA, and the isopropyl ester of 10-phthalimido-3-oxo-5,8-dioxadecanoicacid. The spectral physical constants thereof are given in Table I.

After salification, the corresponding tartrate is obtained.

Yield: 16%

Melting point: 135° C.

Elemental analysis:

    ______________________________________                                                   C    H          N      Cl                                          ______________________________________                                        Theoretical (%)                                                                            49.09  5.30       4.09 5.18                                      Found (%)    49.14  5.28       3.99 5.51                                      ______________________________________                                    

EXAMPLE 36(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2-chloro-3-trifluoromethylphenyl)-3-(4,4-dicyclopropylbutyloxycarbonyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinefumarate

This compound was prepared according to the process described in Example1, stages B and C, using 2-chloro-3-trifluoromethylbenzaldehyde and the4,4-dicyclopropylbutyl ester of 10-phthalimido-3-oxo-5,8-dioxadecanoicacid described in Example 33.

Yield: 10%

Melting point: 122° C.

Elemental analysis:

    ______________________________________                                                   C    H          N      Cl                                          ______________________________________                                        Theoretical (%)                                                                            56.41  5.95       3.76 4.76                                      Found (%)    56.05  6.02       3.76 4.81                                      ______________________________________                                    

The spectral physical constants of the corresponding base are given inTable I.

EXAMPLE 37(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2-chloro-3-trifluoromethylphenyl)-3-{[(E)-4,4-dicyclopropyl-2-butene]oxycarbonyl}-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinefumarate

This compound was prepared according to the process described in Example1, stages B and C, using 2-chloro-3-trifluoromethylbenzaldehyde and the(E)-4,4-dicyclopropyl-2-butenyl ester of10-phthalimido-3-oxo-5,8-dioxadecanoic acid described in Example 29.

Yield: 13%

Melting point: 122° C.

Elemental analysis:

    ______________________________________                                                   C    H          N      Cl                                          ______________________________________                                        Theoretical (%)                                                                            56.57  5.70       3.77 4.77                                      Found (%)    56.29  5.72       3.86 5.14                                      ______________________________________                                    

The spectral physical constants of the corresponding base are given inTable I.

EXAMPLE 38(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2-chloro-3-trifluoromethylphenyl)-3-isobutyloxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinefumarate

This compound was also prepared according to the process described inExample 1, stages B and C, using 2-chloro-3-trifluoromethylbenzaldehydeand the isobutyl ester of 10-phthalimido-3-oxo-5,8-dioxadecanoic aciddescribed in Example 28.

Yield: 17%

Melting point: 118° C.

Elemental analysis:

    ______________________________________                                                   C    H          N      Cl                                          ______________________________________                                        Theoretical (%)                                                                            52.37  5.46       4.21 5.33                                      Found (%)    52.16  5.39       4.21 5.55                                      ______________________________________                                    

The spectral physical constants of the corresponding base are given inTable I.

EXAMPLE 39(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-[(2-methyl-2-propenyl)oxycarbonyl]-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinefumarate Stage A: 2-Methyl-2-propenyl ester of10-phthalimido-3-oxo-5,8-dioxadecanoic acid

This compound was obtained according to the process described in Example25, stage A, but using 2-methylpropen-2-ol instead of isopropyl alcohol.

Yield: 80%

Proton nuclear magnetic resonance spectrum (CDCl₃): 1.75 ppm, s, 3H;3.55 ppm, s, 2H; 3.65 ppm, s, 4H; 3.5-4 ppm, m, 4H; 4.1 ppm, s, 2H; 4.55ppm, s, 2H; 4.95 ppm, m, 2H; 7.5-8.0 ppm, m, 4H.

Stage B

(4R,S)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-[(2-methyl-2-propenyl)oxycarbonyl]-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinefumarate is obtained starting with the ester obtained in the previousstage and with 2,3-dichlorobenzaldehyde and according to the processdescribed in Example 1, stages A and B.

Yield: 21%

Melting point: 116° C.

Elemental analysis:

    ______________________________________                                                    C    H          N      Cl                                         ______________________________________                                        Theoretical (%)                                                                             53.43  5.44       4.45 11.26                                    Found (%)     53.10  5.40       4.29 11.60                                    ______________________________________                                    

The spectral physical constants of the corresponding base are given inTable I.

EXAMPLE 402-{2-[2-(Aminoethoxy)ethoxy]ethyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridineStage A: 11-Phenyl-3,6,10-trioxaundecanamine

0.25 mole of aminoethoxyethanol is added to 295 ml of tetrahydrofurancontaining 0.25 mole of sodium hydride and the mixture is then heatedunder reflux for 30 min. Sodium 4-oxy-5-phenylpentanesulfonate dissolvedin tetrahydrofuran is then added dropwise. The mixture is heated underreflux for approximately 2 hours, hydrolysis is then carried outfollowed by the addition of 10 ml of concentrated sodium hydroxide, thereaction solvent is evaporated off and the residue is taken up with awater:ethyl ether mixture. The solution is exhaustively extracted with1N hydrochloric acid, made alkaline, while cooling, with concentratedsodium hydroxide, extracted with ether, dried and evaporated.

Yield: 32%

Proton nuclear magnetic resonance spectrum (CDCl₃): 1.9 ppm, m, 2H; 2.7ppm, t, 2H; 3.3-3.8 ppm, m, 10H; 4.5 ppm, s, 2H; 7.3 ppm, s, 5H.

Stage B: (11-Phenyl-3,6,10-trioxa-1-undecanyl)phthalimide

0.0395 mole of the amine obtained in the previous stage and 0.0375 moleof phthalic anhydride are heated, with stirring, at 150° C. for 3 hours,removing the water formed. After purification on silica column using adichloromethane:ethyl acetate (90:10) mixture as the eluting solvent,the expected product is obtained.

Yield: 67%

Proton nuclear magnetic resonance spectrum (CDCl₃): 1.7-2.1 ppm, m, 2H;3.4-4.0 ppm, m, 12H; 4.5 ppm, s, 2H; 7.3 ppm, s, 5H; 7.5-8.0 ppm, m, 4H.

Stage C: 4,7-Dioxa-9-phthalimidononanol

40 ml of acetonitrile containing 0.054 mole of boron trifluorideetherate are added to 90 ml of acetonitrile containing 0.0216 mole ofthe compound described above and 0.054 mole of sodium iodide. Thereagents are allowed to remain in contact for one hour at ambienttemperature, the reaction solvent is evaporated off, the residue istaken up with water, extracted with ethyl ether and washed withthiosulfate. After purification on silica column using, at first,dichloromethane and then a dichloromethane:methanol (80:20) mixture asthe eluant, the expected product is obtained.

Yield: 28%

Proton nuclear magnetic resonance spectrum (CDCl₃): 1.6-2.0 ppm, m, 2H;2.1-2.6 ppm, 1H exchangeable; 3.5-4.1 ppm, m, 12H; 7.6-8.0 ppm, m, 4H.

Stage D: 11-Phtalimido-3-oxo-6,9-dioxaundecanoic acid ethyl ester

The alcohol obtained in the previous stage is converted into thecorresponding acid by Jones oxidation. The acid is then subjected to theaction of thionyl chloride, Meldrum's acid and ethanol according to theprocess described in Example 4, Stage A, to obtain the expectedcompound.

Stage E

The2-{2-[2-(2-Aminoethoxy)ethoxy]ethyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methylpyridineis obtained starting with the ester described in stage D and2,3-dichlorobenzaldehyde according to the process described in Example1, stages B and C. The spectral physical constants of this compound aregiven in Table I.

EXAMPLE 41 2-[2-(2-Phtalimidoethoxy)ethoxy]acetic acid Stage A:2-[2-(2-Phtalimidoethoxy)ethoxy]ethanol

188 g of 2-[2-(2-Chloroethoxy)ethoxy]ethanol and 146 g of potassiumphtalimide in 700 ml of dimethylformamide are brought to 95° C. for 17hours.

The mixture is diluted with methylene chloride, washed with saturatedsodium chloride solution, dried and evaporated.

It is distilled in a Kugelrohr, b.p. ₀.05 mmHg: 180°-185° C.

Yield: 90%

Proton nuclear magnetic resonance spectrum (Solvent CDCl₃): 4H(m) 7.5 to8 ppm; 12H(m) 3.4 to 4 ppm; 1H (complex exchangeable D₂ O) 2.5 to 3 ppm.

Stage B

3 g of the alcohol obtained in the preceding stage are dissolved in 150ml of acetone. Jones reagent is introduced while the temperature ismaintained at between 20° and 25° C. The mixture is left to stand for 1hour at room temperature. It is concentrated, then diluted withmethylene chloride and washed with water. It is dried and the solvent isevaporated off to obtain the expected compound.

Melting point: 88°-90° C.

Yield: 90%

Proton nuclear magnetic resonance spectrum (Solvent CDCl₃): 1H (complexexchangeable) 8.8 to 9.5 ppm; 4H(m) 7.6 to 8.1 ppm; 2H(s) 4.1 ppm; 8H(m)3.6 to 4 ppm.

EXAMPLE 42 (R)-2-Phenyl-2-methoxyethanol

72 g of (R)-2-phenyl-2-methoxyacetic acid (prepared according to themethod described in J. Chem. Soc., 1962, p. 1519), are reduced with 16.5g of lithium aluminum hydride in 300 ml of tetrahydrofuran.

The mixture is hydrolysed and the inorganic salts are filtered off, andthe residual oil is then distilled in a Kugelrohr. b.p.₁₅ mmHg =105° C.

Yield: 76%

Proton nuclear magnetic resonance spectrum (Solvent CDCl₃): 5H(m) 7.35ppm; 1H(d) 4.35 ppm; 2H(m) 3.65 ppm; 3H(s) 3.3 ppm; 1H (d exchangeable)2.35 ppm.

Optical rotation in 1% strength solution in ethanol:

    ______________________________________                                               λ (nm)                                                                       [α].sup.24° C.                                      ______________________________________                                               589   -122                                                                    578   -127                                                                    546   -145                                                                    436   -249                                                                    365   -396                                                             ______________________________________                                    

EXAMPLE 43 5,8-Dioxa-3-oxo-10-phthalimidodecanoic acid(R)-2-phenyl-2-methoxyethyl ester

20 g of carbonyldiimidazole are added in a single portion to asuspension containing 34.7 g of the compound of Example 41 in 210 ml ofmethylene chloride.

The mixture is stirred until gaseous evolution has ceased. A mixtureconsisting of 17.7 g of Meldrum's acid and 9.2 g of pyridine in 70 ml ofmethylene chloride is then introduced in a rapid dropwise flow. Themixture is stirred overnight under nitrogen.

The mixture is transferred to a separating funnel, washed with Nsulfuric acid to acid pH and then once with water and dried, and thesolvent is evaporated off.

The oil is taken to a water bath with 25 g of the alcohol obtained inExample 42 until evolution has ceased.

The reaction medium is subjected to chromatography (flashchromatography) on a column containing 1.8 kg of silica, using a mixtureof cyclohexane and ethyl acetate (1:1 V/V) as eluant, to obtain theexpected compound.

Yield: 70%.

Proton nuclear magnetic resonance spectrum (Solvent CDCl₃): 4H(m) 7.6 to8.1 ppm; 5H(s) 7.35 ppm; 3H(m) 4 to 4.6 ppm; 2H(s) 4.1 ppm; 10H(m) 3.5to 4 ppm; 3H(s) 3.3 ppm.

Optical rotation in 1% strength solution in ethanol:

    ______________________________________                                               λ (nm)                                                                       [α].sup.21° C.                                      ______________________________________                                               589   -35.1                                                                   578   -36.5                                                                   546   -41.4                                                                   436   -69.8                                                                   365   -107.2                                                           ______________________________________                                    

EXAMPLE 44 2-(2,3-Dichlorobenzylidene)-3-oxobutanoic acid methyl ester

A mixture containing 8.7 g of 2,3-dichlorobenzaldehyde, 5.8 g of methylacetoacetate, 28 drops of pyridine and 38 drops of hexanoic acid in 280ml of benzene is brought to reflux with stirring for 4 hours. It istransferred to a separating funnel and washed with 10% strength sodiumbicarbonate solution, then with N hydrochloric acid solution and thenwith water. The mixture is dried and evaporated. The crystals obtainedare washed with isopropyl ether.

Yield: 65%

Proton nuclear magnetic resonance spectrum (Solvent CDCl₃): 1H(2s) 8 and8.05 ppm; 3H(m) 7.1 to 7.8 ppm; 3H(2s) 3.9 and 3.75 ppm; 3H(2s) 2.45 and2.2 ppm.

EXAMPLE 45

(4R,4'R/4S,4'R)-4-(2,3-Dichlorophenyl)-5-methoxycarbonyl-3-(2-methoxy-2-phenylethoxycarbonyl)-6-methyl-2-{[2-(2-phthalimidoethoxy)ethoxy]methyl}-1,4-dihydropyridine

A mixture containing 22.2 g of the compound described in Example 44, 38g of the compound described in Example 43 and 6.3 g of ammonium formatein 200 ml of ethanol is stirred under nitrogen at 40° C. for 48 hours.The residual medium is evaporated and purified on a column containing 4kg of silica, using a mixture consisting of methylene chloride and ethylacetate (9:1 V/V) as eluant.

Proton nuclear magnetic resonance spectrum (Solvent CDCl₃): 2H(m) 7.8ppm; 2H(m) 7.7 ppm; 7H(m) 7.3 to 7.1 ppm; 1H(t) 7.05 ppm; 1H(s) 5.45ppm; 2H(m) 4.6 ppm; 11H(m) 3.6 to 4.4 ppm; 3H(2s) 3.6 ppm; 3H(2s) 3.2and 3.05 ppm; 3H(s) 2.3 ppm; 1H(s) not exchangeable with D₂ O, 7.4 ppm.

Optical rotation in 1% strength solution in chloroform:

    ______________________________________                                               λ (nm)                                                                       [α].sup.21° C.                                      ______________________________________                                               589   -13.3                                                                   578   -13.8                                                                   546   -15.1                                                            ______________________________________                                    

EXAMPLE 46(4R,4'R/4S,4'R)-2-[{2-[2-(2-Carboxyphenylcarboxamido)ethoxy]ethoxy}methyl]-4-(2,3-dichlorophenyl)-5-methoxycarbonyl-3-(2-methoxy-2-phenylethoxycarbonyl)-6-methyl-1,4-dihydropyridine

A mixture containing 16.5 g of the compound of Example 45, 100 ml of 10%strength aqueous sodium bicarbonate solution and 230 ml of acetonitrileis brought to reflux with stirring for 24 hours. The solvent isevaporated off and the residue is taken up with water, acidified with Nhydrochloric acid and extracted to obtain the expected compound.

Yield: 87%.

Proton nuclear magnetic resonance spectrum (Solvent CDCl₃): 1H(m) 7.9ppm; 3H(m) 7.5 ppm; 7H(m) 7.4 to 7.15 ppm; 1H(t) 7.05 ppm; 1H(2s) 5.45ppm; 2H(m) 4.8 ppm; 2H(m) 4.4 to 4.1 ppm; 1H(m) 3.9 ppm; 8H(m) 3.8 to3.5 ppm; 3H(2s) 3.6 ppm; 3H(2s) 3.2 and 3.05 ppm; 3H(s) 2.3 ppm; 1H(t)6.55 ppm; 1H (masked signal, exchanged with D₂ O) 7.45 ppm; 1H (flatsignal) 7 to 5 ppm exchanged with D₂ O.

Optical rotation in 1% strength solution in chloroform:

    ______________________________________                                               λ (nm)                                                                       [α].sup.21° C.                                      ______________________________________                                               589   -14.2                                                                   578   -14.8                                                                   546   -16.3                                                            ______________________________________                                    

EXAMPLE 47 Mixture of(-)-2-[{2-[2-(2-carboxyphenylcarboxamido)ethoxy]ethoxy}methyl]-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridineand its homolog substituted at the 5-position with an ethoxycarbonylradical * First Process

The compound of Example 46 is separated into its two isomers by HPLC,using a Lichroprep RP18 50 cm long as column and a mixture of methanoland 0.025M disodium phosphate (55:45 V/V) as eluant, flow rate 10ml/min.

3 g of the second compound derived from the separation are brought toreflux with 30 ml of glyme and 28.6 ml of a 0.26M solution of sodiumethylate. The mixture is evaporated and the residue is taken up withwater, acidified and extracted with ethyl acetate to obtain the expectedcompounds.

Overall yield: 10%

* Second Process Stage A

The compound of Example 45 is chromatographed on a preparative columncontaining 4 kg of silica, using a mixture of methylene chloride andethyl acetate (95:5) as eluant. The first compound derived from theseparation, which is the less polar, is isolated.

Yield: 20%

Proton nuclear magnetic resonance spectrum (Solvent CDCl₃): 2H(m) 7.8ppm; 2H(m) 7.7 ppm; 7H(m) 7.4 to 7.1 ppm; 1H(t) 7.05 ppm; 1H(s) 5.45ppm; 2H(m) 4.4 ppm; 11H(m) 4 to 3.7 ppm; 3H(s) 3.6 ppm; 3H(s) 3.05 ppm;3H(s) 2.3 ppm; 1H(s) 7.45 ppm (exchangeable with D₂ O with difficulty).

Optical rotation in 1% strength solution in chloroform:

    ______________________________________                                               λ (nm)                                                                       [α].sup.21° C.                                      ______________________________________                                               589   -9                                                                      578   -9.6                                                                    546   -10.4                                                            ______________________________________                                    

Stage B

3 g of the compound obtained in the preceding stage are brought toreflux with 30 ml of glyme and 28.6 ml of a 0.26M ethanolic solution ofsodium ethanolate. The mixture is evaporated and the residue is taken upwith water, acidified and extracted with ethyl acetate to obtain theexpected compounds.

Yield: 65%

EXAMPLE 48 Mixture of(-)-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-{[2-(2-phthalimidoethoxy)ethoxy]methyl}-1,4-dihydropyridineand its homolog substituted at the 5-position with an ethoxycarbonylradical

1.9 g of the mixture obtained in Example 47 are dissolved in 30 ml ofmethylene chloride and 0.9 g of carbonyldiimidazole is added in a singleportion. The mixture is left stirred overnight.

The reaction medium is transferred to a separating funnel and washedwith 10% strength sodium bicarbonate and then with N hydrochloric acidand with water. The mixture is dried and evaporated to obtain theexpected compounds.

Yield: 65%

EXAMPLE 49(-)-4-(2,3-Dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-{[2-(2-phthalimidoethoxy)-ethoxy]methyl}-1,4-dihydropyridine

The mixture obtained in Example 48 is separated by preparative HPLC,using a Lichroprep RP 18 column 50 cm long and a mixture of ethanol,water and TFA (500:500:1) as eluant. The expected compound is isolatedfirst.

Yield: 30%

Optical rotation in 1% strength solution in DMSO:

    ______________________________________                                               λ (nm)                                                                       [α].sup.20° C.                                      ______________________________________                                               589   -34.6                                                                   578   -36.5                                                                   546   -43.9                                                                   436   -119.0                                                           ______________________________________                                    

EXAMPLE 50(-)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine

1 g of the compound prepared in Example 49 is refluxed with 10 ml ofethanol and 0.25 ml of hydrazine hydrate for 4 hours. The solvent isevaporated off, the residue is taken up with ethyl ether and washed with5 ml of normal sodium hydroxide and the ether phase is exhaustivelyextracted with N hydrochloric acid. The aqueous phases are thenalkalinized and extracted with ethyl ether to obtain the expectedcompound.

Yield: 60%

Melting point: 69°-71° C.

Proton nuclear magnetic resonance spectrum (Solvent CDCl₃): 1H(m) 7.3 to7.7 ppm exchangeable with D₂ O; 3H(m) 7.6 to 6.9 ppm; 1H(s) 5.5 ppm;2H(s) 4.8 ppm; 2H(q) 4 ppm; 4H(s) 9.7 ppm; 2H(m) 3.4 to 3.7 ppm; 3H(s)3.6 ppm; 2H(t) 2.9 ppm; 3H(s) 2.3 ppm; 2H(m) exchangeable with D₂ O 1.4to 1.8 ppm; 3H(t) 1.2 ppm.

Optical rotation in 1% strength solution in chloroform:

    ______________________________________                                               λ (nm)                                                                       [α].sup.20.5° C.                                    ______________________________________                                               589   -36.5                                                                   578   -38.7                                                                   546   -46.8                                                                   436   -113                                                             ______________________________________                                    

EXAMPLE 51(-)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinefumarate

(-)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridinefumarate is obtained after solubilization of 4.2 g of the compound ofExample 50 in 50 ml of a 0.172M ethanolic solution of fumaric acid. Itis recrystallized in acetonitrile.

Yield: 92%

Melting point: 115° C.

Proton nuclear magnetic resonance spectrum (Solvent CDCl₃ and DMSO-d₆):2H(2d split) 7.3 ppm; 1H(t) 7.1 ppm; 2H(s) 6.7 ppm; 1H(s) 5.45 ppm;2H(m) 4.7 ppm; 2H(q) 4 ppm; 6H(m) 5.7 ppm; 3H(s) 3.6 ppm; 2H(m) 3.1 ppm;3H(s) 2.3 ppm; 3H(t) 1.3 ppm; 1H(s exchanged D₂ O) 7.7 ppm; 4H(sexchanged D₂ O) 5.7 ppm.

Optical rotation in 1% strength solution in DMSO:

    ______________________________________                                               λ (nm)                                                                       [α].sup.20.5° C.                                    ______________________________________                                               589   -33.1                                                                   578   -35.2                                                                   546   -43.0                                                                   436   -134.6                                                           ______________________________________                                    

EXAMPLE 52(-)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine(+)-tartrate

0.2 g of the compound of Example 50 is dissolved in 3.1 ml of a 0.133Methanolic solution of (+)-tartaric acid. After evaporation of thesolvent, 0.24 g of the expected salt is obtained.

Melting point: 150° C.

Optical rotation in 1% strength solution in DMSO:

    ______________________________________                                               λ (nm)                                                                       [α].sup.21.5° C.                                    ______________________________________                                               589   -29.9                                                                   578   -32.5                                                                   546   -40.5                                                                   436   -133.9                                                           ______________________________________                                    

EXAMPLE 53(-)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine(-)-tartrate

0.3 g of the compound of Example 50 is dissolved in 4.6 ml of a 0.133Methanolic solution of (-)-tartaric acid. The expected salt is isolatedafter filtration.

Melting point: 161°-166° C. (sublimation)

Optical rotation in 1% strength solution in DMSO:

    ______________________________________                                               λ (nm)                                                                       [α].sup.21.5° C.                                    ______________________________________                                               589   -32.9                                                                   578   -35                                                                     546   -42.8                                                                   436   -142.4                                                           ______________________________________                                    

EXAMPLE 54(-)-2-{[2-(2-Aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridineracemic tartrate

0.45 g of the compound of Example 50 is dissolved in 6.9 ml of a 0.133Methanolic solution of racemic tartaric acid.

The expected salt is isolated after filtration.

Melting point: 160°-170° C.

Optical rotation in 1% strength solution in DMSO:

    ______________________________________                                               λ (nm)                                                                       [α].sup.21.5° C.                                    ______________________________________                                               589   -31.2                                                                   578   -33.5                                                                   546   -41.1                                                                   436   -135.9                                                           ______________________________________                                    

    TABLE I      COMPOUNDS OF GENERAL FORMULA I      ##STR24##                    NMR (SOLVENT) EX. Ar Y Z Y1 Z1 W U V m n R1 R2 (b): base;     (s): salt      1            ##STR25##      H CH.sub.3 H H CH.sub.3 CH.sub.2 O O 2 2 H H  (DMSO-d.sub.6) (s)1,1     ppm,-t,3H, 2,3 ppm,-s,3H;2.8 to 3.2 ppm,--m,2H;3.3 to 4.7 ppm,--m,11H;4.7      ppm,-s,2H; 5.4 ppm,-s, 1H;6.5 ppm,-s,1H;4H exchangeable 4.9-5.7 ppm   2      ##STR26##      H CH.sub.3 H H CH.sub.3 CH.sub.2 O O 2 2 H H (CDCL.sub.3) (b)1,2     ppm,-s,3H; 2,3 ppm,-s,3H,2,9 ppm,-t,2H; 3,6 ppm,--m,3H3.4-3.7 ppm,--m,2H;3     .7 ppm,-s,4H; 4 ppm,--m,2H,4.7 ppm,- s,2H; 5.1 ppm, -s,1H;     5.9 ppm,-s,2H; 6.5-6.9 ppm,              --m,3H; 1.5 ppm,2H exchange-               able; 7.3 ppm,1H              exchangeable      3            ##STR27##      H CH.sub.3 H H CH.sub.3 CH.sub.2O O 2 2 H H (CDCl.sub.3)(b)1.2 ppm,-t,3H     ; 2.3 ppm,-t,3H;2.9 ppm,-t,2H; 4 ppm,--m,2H;4.7 ppm,-s,2H; 5.1 ppm,-s,1H;6     .5 ppm,-d,1H; 6.8 ppm,-d,1H;1.5 ppm,2H exchangeable; 7.3 ppm,1H exchangea     ble      4            ##STR28##      H      ##STR29##      H H CH.sub.3 CH.sub.2O O 2 H H      5            ##STR30##      H CH.sub.3 H H CH.sub.3 CH.sub.2O O 2 2 H H (CDCl3)(b)(b)1.2 ppm,-t,3H;     2.3 ppm,-s,3H;3.0 ppm,-t,2H; 3.6 ppm,-s,3H;3.7 ppm,-t,2H; 3.9 ppm,-s,4H;4     .2 ppm, --m,2H; 4.7 ppm,-s,2H;5.4 ppm,-s,1H; 7 14 7.6 ppm,4H;       1.7 ppm,2H exchangeable;              7.3 ppm,1H exchangeable   6      ##STR31##      H CH.sub.3 H H CH.sub.3 CH.sub.2O O 2 2 H H (CDCl.sub.3)(b)1.2 ppm,-t,3H     ; 2.3 ppm,-s,3H;2.9 ppm,-t,2H; 3.6 ppm,- s,3H; 3.4-3.7 ppm,-- m,2H; 3.7     ppm,-s,4H;4.0 ppm,--m,2H; 4.8 ppm,-s,2H ;5.5 ppm,-s,1H; 6.9-7.6 ppm,--m,                  3H; 1.4-1.6 ppm,2H exchange-              able; 6.9-7.6     ppm,1H              exchangeable      7            ##STR32##      H CH.sub.3 H H CH.sub.3 CH.sub.2O O 2 2 CH.sub.3 CH.sub.2 (CDCl.sub.3)(b     )1.2 ppm,-t,3H; 2.3 ppm,-d,6H;2.6 ppm,-t,2H; 3.4-3.8 ppm,--m,9H; 4.0     ppm,--m,2H;4.7 ppm,-s,2H; 5.4 ppm,-s,1H; 7.3 ppm,-s,5H; 6.9-7.5 ppm,              --m,5H; 6.9-7.5 ppm,1H              exchangeable      8            ##STR33##      H CH.sub.3 H H CH.sub.3 CH.sub.2O O 2 2 CH.sub.2 CHCH.sub.2 CH.sub.2     CHCH.sub.2 (CDCl.sub.3)(b)1.2 ppm,-t,3H; 2.3 ppm,-s,3H;2.7 ppm,-t,2H;     3.1, ppm,-d,4H:3.5-3.9 ppm,--m,9H; 4.0 ppm,--m,2H; 4.2 ppm, -s,2H;     5.0-5.5 ppm,--m,4H; 5.4 ppm,-s,1H;              5.5-6.5 ppm,--m,2H;     6.9-7.6 ppm,              --m,4H; 6.9-7.6 ppm,1H      9            ##STR34##      H CH.sub.3H      ##STR35##       CH.sub.3 CH.sub.2O O 2 2 H H (CDCl.sub.3)(b)0.0-0.9 ppm,--m,11H,1.2     ppm,-t,3H; 2.3 ppm,-s,3H;2.9 ppm,-t,2H; 3.4-3.7 ppm,--m,2H; 3.7 ppm,-s,4H     ; 4.1 ppm,--m, 2H; 3.9-4.3 ppm,--m,2H ;4.8 ppm,-s,2H; 5.4 ppm,-s,1H;     7     6.9-.5 ppm,--m,4H; 1.4-1.8 ppm,2H              exchangeable; 6.9-7.5     ppm,1H              exchangeable      10            ##STR36##      H CH.sub.3 H H CH.sub.3      OCH.sub.2 CH.sub.2O O 2 2 H H (CDCl.sub.3)(b)1,2 ppm,-t,3H; 3.5     ppm,-s,4H;3,6 ppm,-s,3H; 3.7 ppm,-s,3H;3,4- 3,8 ppm,--m,2H; 4.1 ppm,g,2H;      4.7 ppm,-s,2H;4,8 ppm,-s,2H; 5.5 ppm,-s,1H ;              7.0-7.6       m     ppm,--,3H; 1,9 ppm,              1H exchangeable; 8.5 ppm,     1H exchangeable      11            ##STR37##      H CH.sub.3 H H CH.sub.3 CH.sub.2O O 2 2      ##STR38##      CH.sub.3 (CDCl.sub.3)(s)1.1 ppm,-t,3H; 2.3 ppm,-s,3H;3.5-4.2 ppm,--m,8H;      3.3 ppm,-s,6H; 3.6 ppm,-s,3H; 4 ppm,--m,2H; 4.7 ppm,-s ,2H; 5.1     ppm,-s,2H; 5.4 ppm,-s,1H; 6.9-7.9 ppm,--m,8H; 6.9-7.9 ppm,     1H exchangeable 12      ##STR39##      H CH.sub.3 H H CH.sub.3 CH.sub.2 CH.sub.2 2 3 H H (CDCl.sub.3)(b)1,2     ppm,-t, 1,2-1,8 ppm,--m, 10H; 2,3 ppm,-s,3H; 4.1 ppm,-m,2H;5.4 ppm,-s,1H;      6.9-7.6 ppm,--m,4H; 5.4 ppm,2H exchange-              able; 5.8 ppm,1H                 exchangeable      13            ##STR40##      H      ##STR41##      H H CH.sub.2 CH.sub.2 CH.sub.2 2 3 H H (CDCl.sub.3)(b)0.0-0.9 ppm,--m,11     H;1.2-2.0 ppm,--m,10H;2.4 ppm,- s,3H; 2.5-3.1 ppm,--m,4H; 3.7 ppm,-s,3H;     4.1-4.4 ppm,--m,2H; 5.5 ppm,-s,1H;7.0-7.6 ppm,--m,4H;2.2-4.0 ppm, 2H     exchange-              able; 6.0-6.3 ppm,1H              exchangeable     14      ##STR42##      H CH.sub.3 H H CH.sub.3 CH.sub.2 CH.sub.2 1 2 H H (CDCl.sub.3)(b)1,2     ppm,-t,3H; 1,1-1,9 ppm,--m,4H; 2,3 ppm,-s,3H;2,3-3,0 ppm,--m,4H; 3,6     ppm,-s,3H; 4,1 ppm,--m,2H; 5.4 ppm,-s,1H; 6.9-7.6 ppm, --m,4H; 1.1-             1,9 ppm,2H exchangeable;              6,5 ppm,1H exchangeable     15      ##STR43##      H CH.sub.3 H CH.sub.3 CH.sub.3 CH.sub.2O O 2 2 H H (CDCl3)(b)1,2     ppm,-t,6H; 2.35 ppm,-s,3H; 2,9 ppm,--m, 2H; 3.65ppm,--m,2H; 3.7 ppm,-s,2H     ;4.1 ppm,--m,4H; 4.75 ppm,-s,2H; 5.5 ppm,-s,1H; 1,8ppm,2H exchangeable;     7.7ppm, 1H exchangeable      16            ##STR44##      H CH.sub.3 H CH.sub.3 CH.sub.3 CH.sub.2O O 2 2 H C.sub.3 H.sub.7     (DMSOd.sub.6)(s)0.9 ppm,-t,3H; 1.1 ppm,-t,6H;1.6 ppm,--m,2H; 2.3     ppm,-s,3H; 2.6-3.3 ppm,--m,4H;3.6 ppm,--m,6H; 3.9 ppm,-q,4H: 4.6 ppm,     -s,2H; 5.4ppm,-s,1H; 7.9 and 8.8 ppm,4Hexchangeable      17            ##STR45##      H CH.sub.3 H H CH.sub.3 CH.sub.2O O 2 2 H H (CDCl.sub.3)(b)1.15     ppm,-t,3H; 2.35 ppm,-s,3H; 2,95 ppm,-t,2H; 3.6ppm,-t,2H; 3.65 ppm,-s,4H;3     .75 ppm,-s,3H; 4.15ppm, -q,2H; 4.85 ppm,-s,2H;              5,7 ppm,-s,1H     ; 7.0-8.0 ppm,              --m,4H; 1,8 ppm,2H exchange-     able; 7.0-8.0 ppm,1H              exchangeable      18            ##STR46##      H CH.sub.3 H H CH.sub.3 CH.sub.2O O 2 2 H H (DMSOd.sub.6)(s)1.2     ppm,-t,3H; 2,3 ppm,-s,3H;3 ppm,--m,2H; 3.3-4,5 ppm,--m,13H; 4.7 ppm,-s,2H     ; 4,9ppm,-s,1H; 6.8 ppm,--m,6H; 7.2 ppm,-s,4H; 8.6 ppm,1H     exchangeable      19            ##STR47##      H H H H CH.sub.3 CH.sub.2O O 2 2 H H (CDCl.sub.3)(b)2,3 ppm,-s,3H; 2.9     ppm,--m,2H; 3.55 ppm,--m,2H; 3,6ppm and 3.7 ppm,-2s,10H; 4,7ppm,-s,2H;     5.5 ppm,- s,1H; 2,2ppm,2H exchangeable 7.7ppm, 1H exchangeable  20      ##STR48##      H H H CH.sub.3 CH.sub.3 CH.sub.2O O 2 2 H H (CDCl.sub.3)(b)1.2 ppm,-t,3H     ; 2.35 ppm,-s,3H; 2.5-3.3 ppm,--m,2H;3.55 ppm,--m,2H; 3.6 pmm,-s,3H; 3.7     ppm,-s,4H; 4.05ppm,-q,2H; 4.7 ppm,-s,2H; 5.5ppm,-s,1H; 1.5-2.3 ppm,2Hexch     angeable 7.6 ppm,1H              exchangeable      21            ##STR49##      H CH.sub.3 H H CH.sub.3 CH.sub.2O O 2 2 H COCF.sub.2 (CDCl.sub.3 +     DMSO)(b)1.2 ppm, -t,3H; 2.35 ppm,-s,3H; 3.3-3.9 ppm,--m,4H; 3.6ppm,-s,3H;      3.7 ppm,-s,4H; 4.1ppm,-q,2H; 4.75 ppm,-s,2H;5.5 ppm,-s,1H; 7.8 ppm ,     1Hexchangeable 8,5 ppm, 1Hexchangeable      22            ##STR50##      H CH.sub.3 H H CH.sub.3 CH.sub.2O O 2 2 H H (DMSOd.sub.6)(s)1,2     ppm,-t,3H; 2.3 ppm,-s,3H;2.4 ppm,-s,3H; 3.0 ppm,-t,2H;3.3-3.7 ppm,--m,9H;      3,8 ppm,-s,3H; 4.1 ppm,-q,2H; 4.6ppm,-- m,2H; 5.3 ppm,2,1H;      6.6 ppm,s,2H; 6.8-7.3 ppm,              --m,3H; 7.7 and 8.7 ppm,5H             exchangeable      23            ##STR51##      H      ##STR52##      H H CH.sub.3 CH.sub.2O O 2 2 H H (CDCl.sub.3)(b)2.35 ppm,-s,4H; 2.95     ppm,--m,2H; 3.6 ppm,--m,2H; 3.65ppm,-s,3H; 3.7 ppm,-s,4H4.8 ppm,-s,2H;     5.2 ppm,-s,2H;5.5 ppm,-s,1H; 7.5 ppm, -d,2H;8.3 ppm,-d,2H; 2.0 ppm,2Hexch     angeable 7.9 ppm,1H              exchangeable      24            ##STR53##      H CH.sub.3 H H CH.sub.3 CH.sub.2O  O 3 3 H H (CDCl.sub.3)(b)1.1     ppm,-t,3H; 1,9ppm,--m,4H; 2.3 ppm,-s,3H;2.8 ppm,--m,2H; 3.5ppm,--m,6H;     3,6 ppm,-s,3H;4.1 ppm,-q,2H; 4.6 ppm,-s,2H;5.5 ppm, -s,1H; 7,6 ppm,1Hexch     angeable      25            ##STR54##      CH.sub.3 CH.sub.3 H H CH.sub.3 CH.sub.2O O 2 2 H H (CDCl.sub.3)(b)1.0     and 1.25 ppm,-4d,6H; 2.3ppm,-s,3H; 3.0 ppm,--m,2H;3.5 ppm,--m,2H;     3.6ppm,-s,3H; 3.7 ppm,-s,4H; 4.8ppm,-s,2H; 4.9 ppm,--m,1H;     5.5 ppm,-s,1H; 7.0-7.8              ppm,--m, 3H + 1 exchangeable          1,7 ppm, 1H exchangeable      26            ##STR55##      CH.sub.3 CH.sub.3 H H CH.sub.3 CH.sub.2O O 2 2 H H (CDCl.sub.3)(b)1.0     ppm,-d,3H; 1,2 ppm,-d,3H; 2,3 ppm,-s,3H; 2.6-3,3ppm,--m,2H; 3.55     ppm,--m,2H;3.6 ppm,-s,3H; 3.7 ppm,-s,4H;4.7 ppm,-s,2H; 5.0 ppm, --m,1H;     5.5 ppm,-s,1H; 1.5-2.0ppm,2H exchangeable; 7.7              ppm,1H     exchangeable      27            ##STR56##      CH.sub.3 H H H CH.sub.3 CH.sub.2O O 3 3 H H (CDCl.sub.3)(b)1.2 ppm,-t,3H     ; 1.9ppm,--m,4H; 2.4 ppm,-s,3H;2.8 ppm,--m,2H; 3,4-3,8ppm,--m,6H; 3.6     ppm,-s,3H;4.1 ppm,-q,2H; 4.7 ppm,-s,2H;              5.5 ppm,-s,1H;     6,9-7,6 ppm,              --m,3H; 2,2 ppm,2H exchange-     able; 6.9-7.6 ppm,1H              exchangeable      28            ##STR57##      ##STR58##      H H H CH.sub.3 CH.sub.2O O 2 2 H H (DMSOd.sub.6)(s)0,5-1 ppm,--m,6H;     1-2 ppm,-- m,1H; 2,3 ppm,-s,3H; 2.8-3.2ppm,--m,2H; 3.2-4.0 ppm,--m,11H;     4.7 ppm,-s,2H; 5.4 ppm,-s,1H; 6.5 ppm,-s,2H; 7.5              exchangeabl     e 8.5-9.0 ppm,              1H exchangeable      29            ##STR59##      H      ##STR60##      H H CH.sub.3 CH.sub.2O O 2 2 H H (CDCl.sub.3)(b)0-1.4 ppm,--m,11H;     2.3ppm,-s,3H; 2,9 ppm,--m,2H;3.5 ppm,--m,2H; 3.6 ppm,-s,3H; 3.7 ppm,-s,4H     ; 4.5 ppm,--m,2H; 4.8 ppm,-s,2H; 5.4-5.8ppm,-- m,3H; 6.8-7.7 ppm,--m,3H;     1,2-2,0 ppm,2H exchange-able; 6,8-7,7 ppm, 1Hexchangeable      30            ##STR61##      H CH.sub.3 H H CH.sub.3 CH.sub.2O O 3 3 H H (DMSOd.sub.6)(s)1.15     ppm,-t,3H; 1.5-2,0ppm,--m,4H; 2.3 ppm,-s,6H;2.9 ppm,-t,2H; 3.2-3,7ppm,--m     ,6H; 3,6 ppm,-s,3H;4.1 ppm,-q,2H; 4,5 ppm,-s, 2H;              5.9     ppm,-s,1H; 6,6 ppm,-s,2H;              7.5-7.8 ppm,--m, 3H; 6.6-7.4             ppm,4H exchangeable 8.8              ppm,1H exchangeable   31      ##STR62##      H CH.sub.3 H H CH.sub.3 CH.sub.2O O 2 2 H H (DMSOd.sub.6)(s)1.1     ppm,-t,3H; 2,3 ppm,-s,3H;2.7-3.2 ppm,--m,2H; 3.4-3.7ppm,--m + -s,6H +     3H; 3.8-4.2ppm,-q,2H; 4.6 ppm,-s,2H; 6.5ppm,14 s,2H; 4.7 -5.7 ppm,1H              +5H exchangeable 6.5              ppm,-s,2H; 7.3 ppm,-d,1H; 7.6                  ppm,-d,1H      32            ##STR63##      H CH.sub.3 H H CH.sub.3 CH.sub.2O O 3 3 H H (CDCl.sub.3)(b)1.1 ppm,-t,3H     ; 2.3 ppm,-s,3H;2.9 ppm,--m,2H; 3.6ppm,--m,2H; 3,65 ppm,-s,3H;3.7     ppm,-s,4H; 4.1 ppm,-q,2H;4.7 ppm,-s,2H; 6.0 ppm, -s, 1H;     7.1-7.3 ppm,--m,2H; 1.4 ppm,              2H exchangeable 7.6 ppm,            1H exchangeable      33            ##STR64##      H      ##STR65##      H H CH.sub.3 CH.sub.2O O 2 2 H H (CDCl.sub.3)(b)0.0-0.8 ppm,--m,10H;     1.0-2.2ppm,--m,5H and 2H exchange-able; 2,3 ppm,- s,3H; 2.9ppm,--m,2H;     3.5 ppm,--m,2H;3.6 ppm,-s,3H; 3.7 ppm,-s,4H;4.1 ppm,--m,2H; 4.8 ppm,-s,2H     ; 5.5 ppm,-s,1H; 7.0-7.5              ppm,--m, 3H + 1H exchange-          able      34            ##STR66##      CH.sub.3 H H H CH.sub.3 CH.sub.2O O 2 2 H C.sub.3      H.sub.7 (CDCl.sub.3)(b)0.9 ppm,-t,3H; 1.2 ppm,-t,3H;1.4-2.0 ppm,--m, 3H     + 1Hexchangeable 2.3 ppm,-s,3H;2.4-3.1 ppm,--m,4H; 3.6 ppm,-s,3H;     3.4-3.8 ppm,--m, 6H; 4.1ppm,- q,2H; 4.75 ppm,-s,2H;5.5 ppm,-s,1H; 7.7     ppm,1H              exchangeable      35            ##STR67##      CH.sub.3 CH.sub.3 H H CH.sub.3 CH.sub.2O O 2 2 H H (CDCl.sub.3)(b)0.9     ppm,-d,3H; 1,3ppm,-d,3H; 1.5-2.2 ppm,--m,2H exchangeable 2.3ppm,-s,3H;     2.9 ppm,--m,2H;3.6 ppm,-s,3H; 3.3-3.9 ppm,              --m,6H; 4.7      s     ppm,-,2H; 5.0              ppm,--m,1H; 5.5 ppm,-s,1H;     6.9-8.0 ppm,--m,3H + 1H              exchangeable      36            ##STR68##      H      ##STR69##      H H CH.sub.3 CH.sub.2O O 2 2 H H (CDCl.sub.3)(b)0.0-0.8 ppm,--m,10H;     1.0-2.0ppm,--m,7H + 2H exchange-able; 2.3 ppm,-s,3H; 2.7-3.2 ppm,--m,2H;     3.6 ppm,-s,3H; 3.3-4.2 ppm,--m,8H; 4.8ppm,-s,2H; 5,6 ppm,-s,1H;7.0-8.0     ppm,--m,4H + 1H              exchangeable      37            ##STR70##      H      ##STR71##      H H CH.sub.3 CH.sub.2O  O 2 2 H H (CDCl.sub.3)(b)0,0-1,0 ppm,--m,3H +     2H exchange-able; 2.3 ppm,-s,3H; 2.9ppm,--m,2H; 3.6 ppm,s-,3H;3.3-4.0     ppm,--m,6H; 4.5 ppm,--m,3H; 4.8 ppm,- s,2H; 5.0-6.0ppm, --m,2H; 5.6      s     ppm,-,1H;6.9-7.0 ppm,--m,3H + 1Hexchangeable      38            ##STR72##      H      ##STR73##      H H CH.sub.3 CH.sub.2O O 2 2 H H (CDCl.sub.3)(b)0.45 ppm,-d,3H;     0.55ppm,-d,3H; 1,3-2,2ppm,--m,1H + 2Hexchangeable 2,3ppm,-s,3H; 2.9     ppm,--m,2H;              3.6 ppm,- s,3H; 3.4 -4.0              ppm,--m,8H     ; 4.8 ppm,-s,2H,              5.5 ppm,-s,1H; 7.0-7.8     ppm,--m,3H + 1H              exchangeable      39            ##STR74##      H      ##STR75##      H H CH.sub.3 CH.sub.2O O 2 2 H H (CDCl.sub.3)(b)1.6 ppm,-s,3H; 1.4-1.7     ppm,2H exchangeable; 2.3ppm,-s,3H; 2.6 to 3.3 ppm,--m,2H; 3.6 ppm,-s,3H;     3.3-3.8ppm,--m,6H; 4.5 ppm,-s,2H;              4.7-5.0 ppm,4H; 5.5 ppm,                 -s,1H; 7.0-7.6 ppm,--m,3H + 1H              exchangeable  40      ##STR76##      H CH.sub.3 H H CH.sub.3 (CH.sub.2).sub.2O O 2 2 H H (CDCl.sub.3)(b)1,2     ppm,-t,3H;2,3 ppm,-s,3H; 2,6 ppm,-t,2H;2,9 ppm,--m,2H; 3,4-4.0ppm,--m,8H;      3,6 ppm,-s,3H;3,9 ppm,-q,2H; 5,0 ppm,--m,              3H exchangeable,     5.4 ppm,-s,              1H; 6.9-7.7 ppm,--m,3H

PHARMACOLOGICAL STUDY EXAMPLE 55 Determination of the Vitro Activity inRat Aorta Stimulated by Potassium Ions

This trial was carried out using isolated organs removed from maleWistar rats weighing 300 to 400 g, kept under a water diet 18 hoursbefore sacrificing.

After quickly sacrificing the animal, the aorta (at the level of thearch of the aorta) is removed and dissected into 2 mm-long rings; theendothelium is removed mechanically. After an equilibration period of 1hour in a physiological solution consisting of (mM): NaCl 112, KCl 5,KH₂ PO₄ 1, MgSO₄ 1.2, CaCl₂ 2.5, NaHCO₃ 25 and glucose 11.5, thepreparations are stimulated with a potassium-rich solution. The latterconsists of (mM):NaCl 37, KCl 80, KH₂ PO₄ 1, MgSO₄ 1.2, CaCl₂ 2.5,NaHCO₃ 25 and glucose 11.5. This solution has a pH of 7.4 at 37° C.

After 15 minutes of stabilization, the compounds to be tested are thenadded (sample volume 0.2 ml) at cumulative doses at 60 minutesintervals. From the relaxation values obtained, it is possible toconstruct a doseresponse curve, leading to the calculation of an IC₅₀value (expressed in M).

The results of this study are given in Table II below.

                  TABLE II                                                        ______________________________________                                               8                                                                      COMPOUNDS       IC.sub.50 (M)                                                 ______________________________________                                        EXAMPLE 1       2.5 × 10.sup.-8                                         EXAMPLE 2       3.0 × 10.sup.-8                                         EXAMPLE 3       1.0 × 10.sup.-6                                         EXAMPLE 4       3.0 × 10.sup.-7                                         EXAMPLE 5       6.5 × 10.sup.-8                                         EXAMPLE 6       5.0 × 10.sup.-9                                         EXAMPLE 7       4.0 × 10.sup.-9                                         EXAMPLE 8       6.5 × 10.sup.-9                                         EXAMPLE 9       3.0 × 10.sup.-6                                         EXAMPLE 10      9.0 × 10.sup.-8                                         EXAMPLE 11      2.5 × 10.sup.-7                                         EXAMPLE 12      2.5 × 10.sup.-8                                         EXAMPLE 13      3.0 × 10.sup.-7                                         EXAMPLE 14      4.0 × 10.sup.-8                                         EXAMPLE 15      1.2 × 10.sup.-7                                         EXAMPLE 16      6.1 × 10.sup.-8                                         EXAMPLE 17      7.6 × 10.sup.-9                                         EXAMPLE 18      4.7 × 10.sup.-9                                         EXAMPLE 19      4.9 × 10.sup.-9                                         EXAMPLE 20      2.6 × 10.sup.-8                                         EXAMPLE 21      6.8 × 10.sup.-8                                         EXAMPLE 22      2.0 × 10.sup.-8                                         EXAMPLE 23      2.0 × 10.sup.-7                                         EXAMPLE 24      .sup.  8.2 × 10.sup.-10                                 EXAMPLE 25      1.3 × 10.sup.-8                                         EXAMPLE 26      3.1 × 10.sup.-7                                         EXAMPLE 27      4.4 × 10.sup.-9                                         EXAMPLE 28      9.3 × 10.sup.-9                                         EXAMPLE 29      7.5 × 10.sup.-8                                         EXAMPLE 30      2.5 × 10.sup.-8                                         EXAMPLE 31      1.7 × 10.sup.-7                                         EXAMPLE 32      3.2 × 10.sup.-8                                         EXAMPLE 33      7.7 × 10.sup.-8                                         EXAMPLE 34      1.1 × 10.sup.-9                                         EXAMPLE 35      2.1 × 10.sup.-8                                         EXAMPLE 36      4.7 × 10.sup.-7                                         EXAMPLE 37      3.5 × 10.sup.-7                                         EXAMPLE 38      6.1 × 10.sup.-8                                         EXAMPLE 39      8.0 × 10.sup.-8                                         ______________________________________                                    

EXAMPLE 56 Study in Conscious Dogs with Renal Hypertension

Mongol dogs weighing 20 to 25 kg are used. A Silastic® catheter,inserted under anesthesia at the level of the abdominal aorta, left inposition permanently, enables the arterial pressure to be determinedsubsequently in the conscious animal.

Arterial hypertension is induced by a second operation, underanesthesia, consisting in constricting the left renal artery with aclip, decreasing the flow rate therein by approximately 70%, the leftkidney is also covered with a latex capsule in order to restrictcirculatory compensations; the contralateral kidney is left in position.

The systolic, diastolic and mean arterial pressures are determined witha Statham® P₂₃ pressure sensor attached to the Silastic® catheter andconnected to a Gould® "pressure-processor". The compounds are tested inanimals which became hypertensive in the conscious state at least oneweek after the second operation. The arterial pressure is continuouslyrecorded up to 7 hours after the treatment and then at 24 hours.

The compounds to be tested are administered by the digestive routethrough gastric tubing, in the form of a solution which may be aqueous,aqueous/alcoholic and the like, depending on the solubility of theproducts.

The doses administered are expressed in mg base per body weight kg.

The compounds of the invention were compared with a 1,4-dihydropyridinederivative reference compound, amlodipin. The results of this study aregiven in Table III.

As can be seen from these two tables, the compounds of the presentinvention have an activity comparable to amlodipine, but the period ofaction thereof is much longer.

                  TABLE III                                                       ______________________________________                                                     MEAN ARTERIAL PRESSURE                                                                         AFTER                                                                         TREATMENT                                                  DOSE    CONTROL    Δ mm Hg                                   COMPOUNDS  mg/kg   mm Hg      4 h   7 h  24 h                                 ______________________________________                                        EXAMPLE 1  0.5     133        -21   -22  -15                                             1.0     135        -45   -47  -46                                  EXAMPLE 5  0.5     131        -32   -25  n.d.                                            1.0     128        -48   -39  -10                                  EXAMPLE 6  0.5     136        -20   -29  -11                                             1.0     129        -40   -44  -49                                  EXAMPLE 7  0.5     125         -7    -3  0                                    EXAMPLE 12 2.0     120        -22   -32  n.d.                                 AMLODIPINE 0.5     133        -28   -20  -10                                             1.0     146        -45   -39  -29                                  ______________________________________                                         n.d.: not determined                                                     

EXAMPLE 57 Short-term Studies in Conscious Spontaneous Hypertensive Rats(SHR)

Male spontaneous hypertensive rats weighing 270 to 320 g, aged 16 to 24weeks, are anesthetized with ether. A polyethylene catheter isintroduced into the femoral artery and moved forward to the level of thetail. The pressure in the femoral artery is recorded with a Statham® P₂₃sensor, on a Gould® 2400 recorder. The animals are treated at least onehour after the operation. The compounds are administered orally, in thedissolved form. The doses administered are expressed in mg/kg of base.The compounds of the invention were compared with amlodipine and withanother 1,4-dihydropyridine derivative reference compound, nifedipine.

The results of this study are reported in Table IV. As in the previousexample, the compounds of the present invention are distinguishable fromthe reference compounds by the strength and the duration of theirantihypertensive activity.

                  TABLE IV                                                        ______________________________________                                                     SYSTOLIC                                                                      ARTERIAL PRESSURE                                                                              AFTER                                                                         TREATMENT                                                  DOSE    CONTROL    Δ mm Hg                                   COMPOUNDS  mg/kg   mm Hg      4 h   6 h  24 h                                 ______________________________________                                        EXAMPLE 1  1       208        -44   -54  -47                                             3       212        -79   -78  -71                                  EXAMPLE 2  3       200        -13   -16  n.d.                                 EXAMPLE 5  3       219        -49   -49  -22                                  EXAMPLE 6  1       205        -14   -17  -17                                             3       194        -52   -55  -36                                  EXAMPLE 7  3       207        -22   -16   -8                                  EXAMPLE 8  3       198        -21   -19  n.d.                                 EXAMPLE 12 3       211        -23   -30  -21                                  AMLODIPINE 3       210        -47   -46  -13                                  NIFEDIPINE 3       213        -19   -25  n d.                                 ______________________________________                                         n.d.: not determined                                                     

EXAMPLE 58 Long-term Studies in Conscious Spontaneous Hypertensive rats(SHR)

Male rats weighing 280 to 300 g, aged 16 weeks, are used in this study.The systolic arterial pressure is determined with a Rhema multichannel8,000® apparatus, according to the indirect method, at the tail of theanimal. The compounds to be tested are administered orally, in a singledaily dose.

Determinations of arterial pressure are carried out each day just beforethe treatment. Amlodipine was also studied under the same conditions.The results of this study are reported in Table V below. The resultsshow that, at equal doses, the products of the present invention have ahigher efficiency than amlodipine.

                                      TABLE V                                     __________________________________________________________________________                  SYSTOLIC ARTERIAL PRESSURE                                                           Δ(mm Hg) 24 h AFTER                                                     THE LAST ADMINISTRATION                                           DOSE CONTROL                                                                              OF THE PRODUCTS                                          COMPOUND mg/kg/d                                                                            mm Hg  D.sub.1 *                                                                        D.sub.2 *                                                                        D.sub.3 *                                                                         D.sub.4 *                                                                        D.sub.7 *                                   __________________________________________________________________________    EXAMPLE  1    216    -52                                                                              -51                                                                              -49 -44                                                                              -46                                         EXAMPLE  1    214    -22                                                                              -18                                                                              n.d.                                                                              -17                                                                              -31                                         6                                                                             AMLODIPINE                                                                             1    200     -9                                                                               -8                                                                              -14 -14                                                                               -9                                         __________________________________________________________________________     *D = days                                                                

EXAMPLE 59 Affinity for the Dihydropyridine Binding Site

Study of the displacement by(-)-2-{[2-(2-aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridineand by its racemate of tritiated PN 200-110 bound specifically to thedihydropyridine site associated with the calcium slow channel enabled itto be demonstrated that the compound of Example 50 exhibits an affinityfor these sites which is 30 times as great as its racemate.

This study was carried out on microsomal membrane preparations preparedfrom skeletal muscle of rat (Wistar) hind limbs.

The rats are killed by decapitation. The skeletal muscles are removedand washed in buffer I (20 mM MOPS/KOH pH 7.4, 0.3M sucrose, 1 mM EDTA,0.1 mM iodoacetamide, 1 μM pepstatin A, 1 mg/l leupeptin and 0.1 μMPMSF). The muscles are then mechanically fragmented, taken up in 4volumes of buffer I per gramme of tissue and homogenized.

The homogenate is then centrifuged for 10 minutes at 3,200 g, thepellets are removed and the supernatants are then centrifuged for 20minutes at 15,000 g, and the supernatants are stirred for 15 minutes at4° C. in buffer I containing 0.6M final KCl and then centrifgued for 45minutes at 70,000 g.

The pellets are taken up in buffer I and homogenized in a Potter. Thehomogenates are centrifuged at 100,000 g for 45 minutes and the pelletsthereby obtained correspond to the microsomal fraction used for thestudies of binding and displacement.

The activity of the product is assessed by the displacement of [³ H]-PN200-110, bound specifically to its receptor associated with the calciumslow channel, by increasing concentrations of the test products. Thevalue obtained (K0.5) for each of the products, which represents theconcentration of the product displacing 50% of the [³ H]-PN 200-110,permits calculation of a true dissociation constant (K_(I)): ##EQU1##where [L*] is the concentration of free [³ H]-PN 200-110 and Kd thedissociation constant at equilibrium of the [³ H]-PN 200-110 complex,determined by direct binding.

The K_(I) values of the two products are recorded in Table VI

                  TABLE VI                                                        ______________________________________                                        COMPOUND     K.sub.I EXPRESSED IN nM                                          ______________________________________                                        EXAMPLE 50   0.28 ± 0.15                                                   EXAMPLE 6    8.2 ± 1.7                                                     ______________________________________                                    

EXAMPLE 60 Study on Isolated Rabbit Mesenteric Artery Contracted withCalcium

This test is performed on organs removed from male New Zealand rabbitsweighing 2.5 to 3 kg, subjected to a water regimen for 18 hours beforesacrifice.

After the animal is rapidly sacrificed, the mesenteric artery is removedand dissected into rings 2 mm long; the endothelium is removedmechanically.

After a stabilization period of 90 minutes, the preparations aresubjected to a depolarizing medium (35 mM KCl) without calcium (0.1 mMEGTA) for 15 minutes.

A control series is prepared by adding cumulative doses of calcium tothe bath every 6 minutes until a maximum of effect is produced. Thepreparations are then rinsed for a period of 15 minutes and the productis incubated for one hour before renewal of the calcium series.

A single concentration of the product is tested per organ.

The responses obtained in the presence of product are expressed as apercentage of the maximal value of the control series.

The pD'2 value is calculated according to the method of Van Rossum(1963).

The pD'2 values of the compound of the invention and its racemate appearin Table VII These data show the very marked superiority (more thandouble) of the compound of example 50 compared with its racemate, inpreventing a calcium-induced vascular contraction.

                  TABLE VII                                                       ______________________________________                                               COMPOUND  pD'2                                                         ______________________________________                                               EXAMPLE 50                                                                              7.97                                                                EXAMPLE 6 7.64                                                         ______________________________________                                    

EXAMPLE 61 Study in Unanesthetized Spontaneously Hypertensive Rats (SHR)

SHR male rats weighing 280 to 350 g and aged from 18 to 24 weeks areanaesthetized with imalgene® (150 mg/kg i.p.). Two polyethylenecatheters are introduced, one into the abdominal aorta for the recordingof hemodynamic parameters and the other into the jugular vein for theadministration of the products. The catheters are taken through to necklevel. The animals are used at least 48 hours after surgicalintervention.

The systolic and diastolic abdominal bood pressures are recorded bymeans of a Statham P23XL transducer on a Gould ES 1000 recorder. Theproducts are administered intravenously in a volume of 0.5 ml/kg. Thedoses administered of the test compounds are expressed in mg/kg of base.The blood pressure is recorded in continuous fashion up to 6 hours afterthe treatment.

The changes in systolic blood pressure after treatment are recorded inTable VIII.

The compound of example 50 is distinguished from its racemate by itsactivity, which is more potent and sustained even better over a periodof time, this constituting a considerable advantage in therapy. Ineffect, for the same dose six hours after treatment, the activity of thecompound of the invention is approximately 4 times as great as that ofits racemate.

                  TABLE VIII                                                      ______________________________________                                                           Systolic blood pressure changes                                      DOSE     (ΔmmHg) after treatment                              COMPOUND  (mg/kg)  1H 30 min 3H      6H                                       ______________________________________                                        EXAMPLE 50                                                                              0.1      -16 ± 2                                                                              -18 ± 2                                                                            -21 ± 5                               EXAMPLE 6 0.1      -11 ± 3                                                                               -5 ± 3                                                                             -5 ± 2                               ______________________________________                                    

PHARMACEUTICAL PREPARATION EXAMPLE 62 Capsules containing a 2 mg dose of(4R,S)-2-{[2-(2-aminoethoxy)ethoxy]methyl}-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-pentafluorophenyl-1,4-dihydropyridinehemifumarate (A.E.P.M.D.P.)

A.E.P.M.D.P. . . . 2 mg

Corn starch . . . 15 mg

Lactose . . . 25 mg

Talcum . . . 5 mg

EXAMPLE 63 Tablets containing a 1 mg dose of(-)-2-{[2-(2-aminoethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine(A.D.E.M.M.D.P.)

A.D.E.M.M.D.P. . . . 1 mg

Starch sucrose . . . 64 mg

Cellulose excipient . . . 25 mg

Alginic acid . . . 10 mg

per tablet of theoretical weight 100.00 mg.

We claim:
 1. A process for preparing(-)-2-{[2-(2-Amino-ethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine,the compound of formula XXIV: ##STR77## wherein2-[2-(2-chloroethoxy)ethoxy]ethanol is condensed with potassiumphthalimide, in dimethylformamide in the heated state, to form2-[2-(2-phthalimido-ethoxy)ethoxy]ethanol, the compound of formula XIV:##STR78## which is converted by means of Jones reagent to2-[2-(2-phthalimidoethoxy)ethoxy] acetic acid, the compound of formulaXV ##STR79## which is treated with carbonyldiimidazole and Meldrum'sacid in the presence of pyridine in methylene chloride to obtain thecompound of formula XVI: ##STR80## which is then reacted with(R)-2-phenyl-2-methoxyethanol, the compound of formula XVII ##STR81## toobtain the β-keto ester of formula XVIII ##STR82## which is condensed inthe presence of ammonium formate in ethanol with a benzylidene compoundof formula XIX ##STR83## to obtain(4R,4'R/4S,4'R)-4-(2,3-dichlorophenyl)-5-methoxycarbonyl-3-(2-methoxy-2-phenylethoxycarbonyl)-6-methyl-2-{[2-(2-phthalimidoethoxy)ethoxy]methyl}-1,4-dihydropyridine,the compound of formula XX ##STR84## and then: either: this compound issubjected to the action of aqueous sodium bicarbonate solution to obtain(4R,4'R/4S,4'R)-2-[{2-[2-(2-carboxyphenylcarboxamido)ethoxy]ethoxy}methyl]-4-(2,3-dichlorophenyl)-5-methoxycarbonyl-3-(2-methoxy-2-phenylethoxycarbonyl)-6-methyl-1,4-dihydropyridine,the compound of formula XXI: ##STR85## which is treated after separationby HPLC in the heated state with a mixture of glyme and sodium ethylateto obtain a mixture containing(-)-2-[{2-[2-(2-carboxyphenylcarboxamido)ethoxy]ethoxy}-methyl]-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine,the compound of formula XXII: ##STR86## and its homolog substituted atthe 5-position with an ethoxycarbonyl radical, or: the compound offormula XX is separated by chromatography on a silica column, using amixture of methylene chloride and ethyl acetate (95:5 V/V) as eluant, toobtain the less polar isomer of4-(2,3-dichlorophenyl)-5-methoxycarbonyl-3-(2-methoxy-2-phenylethoxycarbonyl)-6-methyl-2-{[2-(2-phthalimidoethoxy)ethoxy]methyl}-1,4-dihydropyridine,which is then subjected to the action of sodium ethanolate in thepresence of glyme in solution in ethanol to obtain a mixture containingthe compound of formula XXII and its homolog substituted at the5-position with an ethoxycarbonyl radical, which is then subjected tothe action of carbonyldiimidazole in solution in a halogenated alkane atroom temperature to obtain a mixture containing(-)-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-{[2-(2-phthalimidoethoxy)ethoxy]methyl}-1,4-dihydropyridine,the compound of formula XXIII: ##STR87## and its homolog substituted atthe 5-position with an ethoxycarbonyl radical, which mixture is thenseparated by (reverse phase) HPLC to obtain(-)-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-{[2-(2-phthalimidoethoxy)ethoxy]methyl}-1,4-dihydropyridine,which is then brought to reflux in ethanol in the presence of hydrazinehydrate to give the compound of formula XXIV, which can then be salifiedwith a pharmaceutically-compatible organic or inorganic acid.